BR122018070508B1 - Triazole-substituted arylamide derivatives and their use - Google Patents

Abstract

the present invention relates to the compounds of formula (i): i; or a pharmaceutically acceptable salt thereof, wherein, r 1 is optionally substituted triazolyl, and r 2, r 3, r 4, r 5, r 6, r 7 and r 8 are as defined herein. Also disclosed are methods of using the compounds to treat diseases associated with p2x3 and / or p2x2 / 3 receptor antagonists and methods of making the compounds.

Description

Descriptive Report of the Invention Patent for TRIAZOL-SUBSTITUTED ARYLAMIDE DERIVATIVES AND THEIR USE

Divided from PI0821266-0, deposited on December 8, 2008.

[0001] This invention relates to compounds useful for the treatment of diseases associated with purinergic receptor P2X, and more particularly to Ρ2Χβ antagonists and / or P2X _2/3 useful for treating diseases, conditions and genitourinary disorders, pain, inflammation , gastrointestinal and respiratory tract.

[0002] The urinary bladder is responsible for two important physiological functions: storage of urine and emptying of urine. This process involves two main steps: (1) the bladder progressively fills until the tension in its walls rises above a threshold level; and (2) a nervous reflex, called the urination reflex, occurs that empties the bladder or, if it fails, at least causes a conscious urge to urinate. Although the urination reflex is an autonomic reflex of the backbone, it can also be inhibited or mediated by centers in the cerebral cortex or brain.

[0003] Purines, acting through extracellular purinoreceptors, have been implicated as having a variety of physiological and pathological roles. (See, Burnstock (1993) Drug Dev. Res. 28: 195-206). ATP, and to a lesser extent, adenosine, can stimulate the terminals of the sensory nerves which results in intense pain and a marked increase in the discharge of the sensory nerves. ATP receptors have been classified into two main families, the P2Y and P2X purinoreceptors, based on molecular structure, transduction mechanisms, and pharmacological characterization. P2Y purinoreceptors are G protein coupled receptors, while P2X purinoreceptors are a family of ATP-activated cation channels. Purinergic receptors, in particular, P2X receptors, are known to form homomultimers or heteromultimers. So far, cDNAs for several P2X receptor subtypes have been cloned, including: six homomeric receptors, Ρ2Χι; P2X ₂ ; P2X3; P2X <P2Xs; and Ρ2Χγ; and three heteromeric receptors P2X _2/3, P2X4 / 6, P2X1 / 5 (See, e.g., Chen et al. (1995) 870 180 137 880 NatuPetição, the 10/04/2018, p. 14/114

2/98 re 377: 428-431; Lewis et al. (1995) Nature 377: 432-435; and Burnstock (1997) Neurophamacol. 36: 1127-1139). The structural and chromosomal map of the genomic subunit of the mouse P2X ₃ receptor has also been described (Souslova et al. (1997) Gene 195: 101-111). In vitro coexpression of the P2X ₂ and P2X ₃ receptor subunits is necessary to produce ATP-activated currents with the properties seen in some sensory neurons (Lewis et al. (1995) Nature 377: 432-435).

[0004] P2X receptor subunits are found in afferents in the rodent and human bladder urothelium. There are data suggesting that ATP may be released from epithelial / endothelial cells of the urinary bladder or other hollow organs as a result of distension (Burnstock (1999) J. Anatomy 194: 335-342; and Ferguson et al. (1997) J. Physiol. 505: 503-511). ATP released in this way can serve a role in transporting information to sensory neurons located in subepithelial components, for example, suburothelial lamina propria (Namasivayam, et al. (1999) BJU Intl. 84: 854-860). P2X receptors have been studied on several neurons, including sensory, sympathetic, parasympathetic, mesenteric, and central (Zhong, et al. (1998) Br. J. Pharmacol. 125: 771-781). These studies indicate that purinergic receptors play a role in the neurotransmission of bladder afferents, and that modulators of P2X receptors are potentially useful in the treatment of bladder disorders and other diseases or genitourinary conditions.

[0005] Recent evidence also suggests a role for endogenous ATP and purinergic receptors in nociceptive responses in mice (Tsuda et al. (1999) Br. J. Pharmacol. 128: 1497-1504). ATP-induced activation of P2X receptors at the nerve terminals of the dorsal root ganglion in the backbone has been shown to stimulate the release of glutamate, a key neurotransmitter involved in nociceptive signaling (Gu and MacDermott, Nature 389: 749-753 (1997)) . P2X ₃ receptors have been identified in nociceptive neurons in the dental pulp (Cook et al., Nature 387: 505508 (1997)). ATP released from damaged cells may thus lead to pain by activating P2X ₃ containing receptors and / or P2X _2/3 in nerve endings

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3/98 nociceptive sensory. This is consistent with pain induction by ATP applied intradermally in the human bubble-based model (Bleehen, Br J Pharmacol 62: 573-577 (1978)). P2X antagonists have been shown to be analgesics in animal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol 350: 618-625 (1994)). This evidence suggests that P2X ₂ and P2X ₃ are involved in nociception, and that P2X receptor modulators are potentially useful as analgesics.

[0006] Other researchers have shown that P2X ₃ receptors are expressed in the human colon, and expressed at higher levels in the inflamed colon than in the normal colon (Yiangou et al, Neurogastroenterol Mot (2001) 13: 365-69). Other researchers have implicated the P2X ₃ receptor in detecting distal or intraluminal pressure in the intestine, and initiating reflexive contractions (Bian et al., J Physiol (2003) 551.1: 309-22), and have linked this to colitis (Wynn et al. , Am J Physiol Gastrointest Liver Physiol (2004) 287: G647-57).

[0007] Brouns et al. (Am J Respir Cell Mol Biol (2000) 23: 52-61) found that P2X ₃ receptors are expressed in pulmonary neuroepithelial bodies (NEBs), implicating the receptor in the transmission of pain in the lung. More recently, others have implicated P2X ₂ and P2X ₃ receptors in the detection of pO2 in pulmonary NEBs (Rong et al., J Neurosci (2003) 23 (36): 11315-21).

[0008] Accordingly, there is a need for compounds that act as modulators of P2X receptors, including antagonists of P2X ₃ receptor and P2X _2/3, as well as a need for methods of treating diseases, conditions and disorders mediated by P2X ₃ receptor , and / or P2X _2/3. The present invention satisfies these needs as well as others.

[0009] The invention provides compounds of formula I:

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4/98 or pharmaceutically acceptable salts thereof, where:

R ¹ is optionally substituted triazolyl;

R ² is optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridazinyl or optionally substituted thiophenyl;

R ³ is hydrogen; C1-6alkyl; hetero-C1-6alkyl; or cyan;

R ⁴ is hydrogen; C1-6alkyl; or hetero-C1-6alkyl;

or R ³ and R ⁴ together with the atom to which they are attached can form a C3-6 carbocyclic ring;

R ⁵ is C1-6 alkyl; hetero-C1-6alkyl; halo-C1-6alkyl; N-C1-6 alkylamino; N, N-di- (C1-6 alkyl) -amino; C3-7Cycloalkyl; aryl; heteroaryl; heterocyclyl; C3-7Cycloalkyl-C1-6alkyl; heteroaryl-C1-6alkyl; heterocyclyl-C1-6alkyl; aryl-C1-6alkyl; aryloxy-C1-6alkyl; - (CR ^to R ^b ) _m -C (O) -R ⁸ 'where m is 0 or 1; R ^a and R ^b each independently is hydrogen; or C1-6alkyl; and R ⁸ 'is hydrogen; C1-6alkyl; hetero-C1-6alkyl; C3-7Cycloalkyl; aryl; heteroaryl; heterocyclyl; C3-7Cycloalkyl-C1-6alkyl; aryl-C1-6alkyl; heteroaryl-C1-6alkyl; heterocyclyl-C1-6alkyl; C3-7Cycloalkyloxy; aryloxy; heteroaryloxy; heterocyclyloxy; C3-7Cycloalkyloxy-C1-6alkyl; aryloxy-C1-6alkyl; heteroaryloxy-C1-6alkyl; heterocyclyloxy-C1-6alkyl; or -NR ⁹ R ¹⁰ , where R ⁹ is hydrogen; or C1-6alkyl; and R ¹⁰ is hydrogen; C1-6alkyl; hetero-C1-6alkyl; C3-7Cycloalkyl; aryl; heteroaryl; heterocyclyl; C3-7Cycloalkyl-C1-6alkyl; aryl-C1-6alkyl; heteroaryl-C1-6alkyl; or heterocyclyl-C1-6alkyl;

or R ⁴ and R ⁵ together with the atom to which they are attached can form a C3-6 carbocyclic ring which is optionally substituted with hydroxy;

or R ⁴ and R ⁵ together with the atom to which they are attached can form a C4-6 heterocyclic ring containing one or two hetero atoms each independently selected from O, N and S;

or R ³ , R ⁴ and R ⁵ together with the atom to which they are attached can form a six-membered heteroaryl containing one or two nitrogen atoms, and which are optionally substituted with halo, amino or C1-6 alkyl; and

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5/98

R ⁶ , R ⁷ and R ⁸ each independently is hydrogen; C1-6alkyl; C1-6 alkyloxy; halo; C1-6haloalkyl; or cyan.

[00010] The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.

[00011] Unless otherwise stated, the following terms used in this Order, including in the specification and in the claims, have the definitions given below. It should be noted that, as used in the specification and the appended claims, the singular forms one, one, and o / a include plural referents unless the context clearly dictates otherwise.

[00012] Agonist refers to a compound that enhances the activity of another compound or receptor site.

[00013] Alkyl means the half of monovalent linear or branched saturated hydrocarbon, consisting only of carbon and hydrogen atoms, having from one to twelve carbon atoms. Lower alkyl refers to an alkyl group of one to six carbon atoms, that is, C1-6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

[00014] Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, for example, ethylene, propenyl, and the like. [00015] Alquinyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, for example, ethynyl, propynyl, and the like.

[00016] Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched divalent saturated hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene,

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6/98 pentylene, and the like.

[00017] Alkoxy and alkyloxy, which can be used interchangeably, mean a half of the formula -OR, where R is an alkyl half as defined here. Examples of alkoxy halves include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[00018] Alkoxyalkyl means one half of the formula R ^a -OR ^b -, where R ^a is alkyl and R ^b is alkylene as defined here. Exemplary alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2-methoxyethyl) -3-methoxypropyl.

[00019] Alkylcarbonyl means a half of the formula -R'-R where R 'is oxo and R is alkyl as defined here.

[00020] Alkylsulfonyl means one half of the formula -R'-R where R 'is -SO2- and R is alkyl as defined here.

[00021] Alkylsulfonylalkyl means one half of the formula -R'-R-R 'where R' is alkylene, R is -SO2- and R 'is alkyl as defined here.

[00022] Amino means one half of the formula -NRR 'where R and R' each independently is hydrogen or alkyl as defined here. Amino thus includes alkylamino (where one of R and R 'is alkyl and the other is hydrogen) and dialkylamino (where R and R' are both alkyl).

[00023] Alkoxyamino means one half of the formula -NR-OR 'where R is hydrogen or alkyl and R' is alkyl as defined here.

[00024] Alkylsulfanyl means one half of the formula -SR where R is alkyl as defined here.

[00025] Aminoalkyl means a group -R-R 'where R' is amino and R is alkylene as defined here. Aminoalkyl includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino half of aminoalkyl can be substituted once or twice with alkyl to provide alkylaminoalkyl and dialkylaminoalkyl respectively. Alkylaminoalkyl includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. Dialkylaminoalkyl includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

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7/98 [00026] Aminoalkoxy means a group -OR-R 'in which R' is amino and R is alkylene as defined herein.

[00027] Alkylsulfonyl starch means one half of the formula -NR'SO2-R where R is alkyl and R 'is hydrogen or alkyl.

[00028] Aminocarbonyloxyalkyl or carbamylalkyl means a group of the formula -R-O-C (O) -NR'R where R is alkylene and R ', R each independently is hydrogen or alkyl as defined herein.

[00029] Alquinylalkoxy means a group of the formula -O-R-R 'where R is alkylene and R' is alkynyl as defined herein.

[00030] The antagonist refers to a compound that decreases or prevents the action of another compound or receptor site.

[00031] Arila means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono, bi or tricyclic aromatic ring. The aryl group can be optionally substituted as defined here. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxyphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, benzene, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl , benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof, each being optionally substituted.

[00032] Arylalkyl and Aralkyl which can be used interchangeably, mean a radical -R ^to R ^b where R ^a is an alkylene group and R ^b is an aryl group as defined here; for example, phenylalkyls such as benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and others are examples of arylalkyl. [00033] Arylsulfonyl means a group of the formula -SO2-R where R is aryl as defined here.

[00034] Aryloxy means a group of the formula -O-R where R is aryl as defined here.

[00035] Aralkyloxy means a group of the formula -O-R-R where R is alkylene and R 'is aryl as defined here.

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8/98 [00036] Cyanoalkyl means one half of the formula -R'-R where R 'is alkylene as defined here and R is cyan or nitrile.

[00037] Cycloalkyl means a monovalent saturated carbocyclic moiety consisting of mono or bicyclic rings. Cycloalkyl may be optionally substituted with one or more substituents, each substituent being independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof.

[00038] Cycloalkylalkyl means one half of the formula -R'-R where R 'is alkylene and R is cycloalkyl as defined here.

[00039] Heteroalkyl means an alkyl radical as defined here in which one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of OR ^a , -NR ^b R ^c , and -S (O) _n R ^d (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, where R ^a is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl ; R ^b and R ^c are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and when n is 0, R ^d is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R ^d is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylamino. Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethyl, 2,3-dihydroxypropyl, 1-hydroxymethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

[00040] Heteroaryl means a monocyclic or bicyclic radical of 5 to atoms in the ring having at least one aromatic ring containing one, two, or three heteroatoms in the ring selected from N, O, or S, the remaining atoms in the ring being C, with the understanding that the connection point of the

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9/98 radical heteroaryl will be in an aromatic ring. The heteroaryl ring can be optionally substituted as defined here. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine, pyridine , isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranil, benzimidazolyl, benzo-oxazolyl, benzo-oxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, quininyl, quinolinyl, quinolinyl, quinoline, quinoline , acridinyl and the like, including partially hydrogenated derivatives thereof, each optionally substituted.

[00041] Heteroarylalkyl or heteroaralkyl means a group of the formula -R-R 'where R is alkylene and R' is heteroaryl as defined herein. [00042] Heteroarylsulfonyl means a group of the formula -SO2-R where R is heteroaryl as defined here.

[00043] Heteroaryloxy means a group of the formula -O-R where R is heteroaryl as defined here.

[00044] Heteroaralkyloxy means a group of the formula -O-R-R where R is alkylene and R 'is heteroaryl as defined herein.

[00045] The terms halo, halogen and halide which can be used interchangeably, refer to a substituent of fluorine, chlorine, bromine, or iodine. [00046] Haloalkyl means alkyl as defined here in which one or more hydrogens have been replaced with the same or different halogen. Exemplary haloalkyls include -CH2CI, -CH2CF3, -CH2CCI3, perfluoroalkyl (e.g., -CF3), and the like.

[00047] Haloalkoxy means a half of the formula -OR, where R is a haloalkyl half as defined here. An exemplary haloalkoxy is difluoromethoxy.

[00048] Heterocycloamino means a saturated ring in which at least one atom in the ring is N, NH or N-alkyl and the remaining atoms in the ring form an alkylene group.

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10/98 [00049] Heterocyclyl means a monovalent saturated half, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring can be optionally substituted as defined here. Examples of heterocyclyl halves include, but are not limited to, optionally substituted piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, quinazolidinyl, quinazolidinyl, quinoline , isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorfolinylsulfoxide, tiamorfolinylsulfine, taminorinolinquinquinone

[00050] Heterocyclylalkyl means one half of the formula -R-R 'where R is alkylene and R' is heterocyclyl as defined here.

[00051] Heterocyclyloxy means one half of the formula -OR where R is heterocyclyl as defined here.

[00052] Heterocyclylalkoxy means one half of the formula -OR-R 'where R is alkylene and R' is heterocyclyl as defined here.

[00053] Hydroxyalkoxy means a half of the formula -OR where R is hydroxyalkyl as defined here.

[00054] Hydroxyalkylamino means one half of the formula -NR-R 'where R is hydrogen or alkyl and R' is hydroxyalkyl as defined here. [00055] Hydroxyalkylaminoalkyl means one half of the formula -RNR'-R where R is alkylene, R 'is hydrogen or alkyl, and R is hydroxyalkyl as defined here.

[00056] Hydroxycarbonylalkyl or carboxyalkyl means a group of the formula -R- (CO) -OH where R is alkylene as defined herein.

[00057] Hydroxyalkyloxycarbonylalkyl or hydroxyalkoxycarbonylalkyl means a group of the formula -R-C (O) -O-R-OH in which each R is alkylene and can be the same or different.

[00058] Hydroxyalkyl means a half of alkyl as defined

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11/98 here, substituted with one or more, preferably one, two or three hydroxy groups, as long as the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1 - (hydroxymethyl) 2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-di -hydroxypropyl, 2-hydroxy-1-hydroxymethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.

[00059] Hydroxycycloalkyl means a cycloalkyl moiety as defined here in which one, two or three hydrogen atoms have been replaced in the cycloalkyl radical with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

[00060] Urea or ureide means a group of the formula -NR'-C (O) NRR 'where R', R and R 'each independently is hydrogen or alkyl.

[00061] Carbamate means a group of the formula -O-C (O) -NR'R where R 'and R each independently is hydrogen or alkyl.

[00062] Carboxy means a group of the formula -O-C (O) -OH.

[00063] Sulfonamido means a group of the formula -SO2-NR'R in which R ', R and R' each independently is hydrogen or alkyl.

[00064] Optionally substituted, when used in combination with aryl, phenyl, heteroaryl cycloalkyl or heterocyclyl, means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl which are optionally substituted independently of the other four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyan, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, -COR, -SO2yl (where R is hydrogen, - (CR'R) _n -COOR (where n is an integer from 0 to 5, R 'and R are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or - ( CR'R) _n -CONR ^a R ^b (where n is an integer from 0 to 5, R 'and R are independently hydrogen or alkylPetition 870180137880, 10/4/2018, page 24/114

12/98 la, and R ^a and R ^b are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optional substituents for aryl, phenyl, heteroaryl cycloalkyl or heterocyclyl include alkyl, halo, haloalkyl, alkoxy, cyano, amino and alkylsulfonyl. Most preferred substituents are methyl, fluorine, chlorine, trifluoromethyl, methoxy, amino and methanesulfonyl.

[00065] Leaving group means the group with the meaning conventionally associated with it in synthetic organic chemistry, that is, an atom or group displaceable under substitution reaction conditions. Examples of starting groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and optionally substituted, isopropyl, benzoyloxy, similarly, isopropyl.

[00066] Modulator means a molecule that interacts with a target. Interactions include, but are not limited to, agonist, antagonist, and the like, as defined here.

[00067] Optionally or optionally means that the subsequently described event or circumstance may, but does not need to, occur, and that the description includes circumstances where the event or circumstance occurs and circumstances in which it does not.

[00068] Illness and Illness status means any disease, condition, symptom, disorder or indication.

[00069] Inert organic solvent or inert solvent means the solvent is inert under the conditions of the reaction being described in conjunction with, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N, Ndimethylformamide, chloroform, methylene chloride or dichloromethane , dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless otherwise specified, the solvents used in the reactions of the present invention are inert solvents.

[00070] Pharmaceutically acceptable means that it is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and neither

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13/98 biologically otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

[00071] Pharmaceutically acceptable salts of a compound means salts that are pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of the parent compound. Such salts include:

[00072] acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoeptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxinaftoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or [00073] salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

[00074] Preferred pharmaceutically acceptable salts are salts formed of acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.

[00075] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) as defined herein, of the same acid addition salt.

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14/98 [00076] Protecting group or protecting group means the group that selectively blocks a reactive site in a multifunctional compound, so that a chemical reaction can be carried out selectively at another reactive site unprotected in the meaning conventionally associated with it in synthetic chemistry . Certain processes of this invention have protective groups to block reactive nitrogen and / or oxygen atoms present in the reagents. For example, the terms amino protection group and nitrogen protection group are used interchangeably here and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to select a group for ease of removal and the ability to withstand the following reactions.

[00077] Solvates means forms of solvent addition that either contain stoichiometric or non-stoichiometric amounts of the solvent. Some compounds have a tendency to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one of the substances in which water retains its molecular state as H2O, such a combination being able to form one or more hydrates.

[00078] Individual means mammals and non-mammals. Mammals means any member of the Mammalia class including, but not limited to, human beings; non-human primates such as chimpanzees and other monkeys and monkey species; farm animals such as oxen, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include,

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15/98 but are not limited to, birds, and the like. The term subject does not denote a particular age or sex.

[00079] Urinary tract disorders or uropathy used interchangeably with urinary tract symptoms signify pathological changes in the urinary tract. Examples of urinary tract disorders include, but are not limited to, incontinence, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyper reflexia, outlet obstruction, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, incontinence urinary urgency, urethritis, prostatodynia, cystitis, idiopathic bladder hypersensitivity, and the like.

[00080] States of disease associated with the urinary tract or disease of the states of the urinary tract or uropathy used interchangeably with symptoms of the urinary tract signify pathological changes in the urinary tract, or dysfunction of the urinary bladder smooth muscle or its innervation causing disorderly urinary storage or emptying formation. Symptoms of the urinary tract include, but are not limited to, overactive bladder (also known as detrusor hyperactivity), outlet obstruction, outlet failure, and pelvic hypersensitivity.

[00081] Overactive bladder or detrusor hyperactivity include, but are not limited to, symptomatic manifestations such as urgency, frequency, altered bladder capacity, incontinence, urination threshold, unstable bladder contractions, sphincteric spasticity, detrusor hyperreflexia (bladder) neurogenic), detrusor instability, and the like.

[00082] Outflow obstruction includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral narrowing disease, tumors, low flow rates, difficulty in initiating urination, urgency, suprapubic pain, and the like.

[00083] Outlet failure includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, mixed incontinence, stress urinary incontinence, and the like.

[00084] Pelvic hypersensitivity includes, but is not limited to, pelvic painPetition 870180137880, from 10/04/2018, pg. 11/28

16/98 vica, interstitial (cell) cystitis, prostatodynia, prostatitis, vulvadinia, urethritis, orchidgia, overactive bladder, and the like.

[00085] Respiratory disorder refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like. [00086] Gastrointestinal disorder (GI disorder) refers to, without limitation, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, IBS dominant diarrhea, associated pain GI distension, and the like.

[00087] Pain includes, without limitation, inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve damage; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; posttraumatic injury; or pain associated with irritable bowel syndrome.

[00088] Therapeutically effective amount means an amount of a compound which, when administered to a subject to treat a disease state, is sufficient to carry out such treatment for the disease state. The therapeutically effective amount will vary, depending on the compound, the disease state being treated, the severity or disease treated, the age and relative health of the subject, the route and method of administration, the judgment of the attending physician or veterinarian, and others factors. [00089] The terms those defined above and those defined here when referring to a variable are incorporated by reference to the broad definition of the variable as well as preferred, most preferred and most preferred definitions, if any.

[00090] Treating or treating a disease state includes: [00091] preventing the disease state, that is, preventing the clinical symptoms of the disease state from developing in a subject who may be exposed or predisposed to the disease state disease, but does not yet experience or exhibit symptoms of the disease state.

[00092] inhibit the disease state, that is, arrest the development of the disease state or its clinical symptoms, or

Petition 870180137880, of 10/04/2018, p. 11/294

17/98 [00093] alleviate the disease state, that is, causing temporary or permanent regression of the disease state or its clinical symptoms.

[00094] The terms treating, contacting and reacting when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and / or desired product. It should be appreciated that the reaction that produces the indicated and / or desired product may not necessarily be the result directly of the combination of two reagents that were added initially, that is, there may be one or more intermediates that are produced in the mixture that ultimately takes formation of the indicated and / or desired product.

[00095] In general, the nomenclature used in this Order is based on AUTONOM® v. 4.0, a Beilstein Institute computerized system for generating the systematic IUPAC nomenclature. The chemical structures shown here were prepared using ISIS® version 2.2. Any open valence that appears on a carbon, oxygen, sulfur or nitrogen atom in the structures here indicates the presence of a hydrogen atom unless otherwise indicated. Where a nitrogen-containing heteroaryl ring is shown with an open valence on a nitrogen atom, and variables such as R ^a , R ^b or R ^c are shown on the heteroaryl ring, such variables can be linked to or joined with open valence nitrogen . Where a chiral center exists in a structure, but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are covered by the structure. Where a structure shown here can exist in multiple tautomeric forms, all such tautomers are covered by the structure.

[00096] All patents and publications identified here are hereby incorporated by reference in their entirety.

[00097] In many embodiments of formula I, R ¹ is optionally substituted triazolyl once or twice, and more preferably once, with

C1-6alkyl.

[00098] In many embodiments of formula I, R ¹ is triazolyl substituted once with Ci-6alkyl.

Petition 870180137880, of 10/04/2018, p. 11/30

18/98 [00099] In certain embodiments of formula I, R ¹ is optionally substituted once or twice, preferably once, with C1-6alkyl, halo-C1-6alkyl, hetero-C1-6alkyl, C1-6alkoxy, amino, phenyl, heterocyclyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-6alkyl or cyano.

[000100] In certain embodiments of formula I, R ¹ is triazolyl optionally substituted once with C1-6alkyl, halo-C1-6alkyl, hetero-C1-6alkyl, C1-6alkoxy, amino, phenyl, heterocyclyl, C3-6-cycloalkyl , C3-6Cycloalkyl-C1-6 alkyl or cyano.

[000101] In certain embodiments of formula I, R ¹ is triazolyl optionally substituted once with halo-C 1-6 alkyl.

[000102] In certain embodiments of formula I, R ¹ is triazolyl substituted once with -Ci-6alkyl or halo-C1-6alkyl.

[000103] In certain embodiments of formula I, R ¹ is triazolyl substituted once with hetero-C1-6alkyl selected from hydroxy-C1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkylamino-C1-6alkyl, or N, N- di- (C1-6alkyl) -amino-C1-6alkyl.

[000104] In certain embodiments of formula I, R ¹ is triazolyl optionally substituted once with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl , fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy , dimethylamino, azetidin-2-yl, 1-methyl-azetidin-2-yl, 1-dimethylaminoethyl or dimethylamino-methyl.

[000105] In certain modalities of formula I, R ¹ is triazolyl substituted once with C1-6alkyl selected from methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopropylmethyl. [000106] In certain modalities of formula I, R ¹ is triazolyl optionally substituted once with halo-C 1-6 alkyl selected from trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl or 2,2-difluoroethyl.

[000107] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,3] triazolyl.

Petition 870180137880, of 10/04/2018, p. 11/314

19/98 [000108] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,3] triazol-1-yl.

[000109] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,3] triazol-2-yl.

[000110] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,3] triazol-5-yl.

[000111] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,4] triazolyl.

[000112] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,4] triazol-1-yl.

[000113] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,4] triazol-4-yl.

[000114] In certain embodiments of formula I, R ¹ is optionally substituted [1,2,4] triazol-3-yl.

[000115] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1-yl optionally substituted with C 1-6 alkyl.

[000116] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1-yl optionally substituted with C1-6alkyl, halo-C1-6alkyl, hetero-C1-6alkyl, C3-6 -cycloalkyl, C3-6Cycloalkyl-C1-6alkyl or cyano.

[000117] In certain embodiments of formula I, R ¹ is [1,2,4] triazole-1 -yl optionally substituted with halo-C1-6alkyl.

[000118] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1 -yl optionally substituted with hetero-C1-6alkyl selected from hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, Ci -6alkylamino-C1-6alkyl, or N, N-di- (C1-6alkyl) -aminoC1-6alkyl.

[000119] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1-yl optionally substituted with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methyl-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy, dimethylamino, azetidin-2-yl, 1-methyl-azetidin-2-yl, 1-dimethylaminoethyl or dimethylamino-methyl.

Petition 870180137880, of 10/04/2018, p. 11/32

20/98 [000120] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1 -yl optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , cyclopropyl or cyclopropylmethyl.

[000121] In certain embodiments of formula I, R ¹ is [1,2,3] triazole-1 -yl optionally substituted with C1-6alkyl.

[000122] In certain embodiments of formula I, R ¹ is [1,2,3] triazol-1 -yl optionally substituted with C1-6alkyl, halo-C1-6alkyl, hetero-C1-6alkyl, C3-6cycloalkyl, C3- 6Cycloalkyl-C1-6alkyl or cyano.

[000123] In certain embodiments of formula I, R ¹ is [1,2,3] triazole-1-yl optionally substituted with halo-C 1-6 alkyl.

[000124] In certain embodiments of formula I, R ¹ is [1,2,3] triazol-1 -yl optionally substituted with hetero-C1-6alkyl selected from hydroxy-C1-6alkyl, C1-6alkoxy-C1-6alkyl, Ci -6alkylamino-C1-6alkyl, or N, N-di- (C1-6alkyl) -aminoC1-6alkyl.

[000125] In certain embodiments of formula I, R ¹ is [1,2,3] triazol-1 -yl optionally substituted with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy, dimethylamino, azetidin-2-yl, 1-methyl-azetidin-2-yl, 1-dimethylamino-ethyl or dimethylamino-methyl.

[000126] In certain embodiments of formula I, R ¹ is [1,2,3] triazol-1 -yl optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl or cyclopropylmethyl.

[000127] In certain embodiments of formula I, R ¹ is [1,2,4] triazole-1 -yl optionally substituted in position 5 with C1-6alkyl.

[000128] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1 -yl optionally substituted in position 5 with C1-6alkyl, halo-C1-6alkyl, hetero-C1-6 alkyl, C3- 6-cycloalkyl, C3-6Cycloalkyl-C1-6alkyl or cyano.

[000129] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1 -yl optionally substituted in position 5 with halo-C1-6alkyl.

[000130] In certain modalities of formula I, R ¹ is [1,2,4] triazole-1-il opcioPetição 870180137880, from 10/04/2018, p. 11/33

21/98 finally substituted in position 5 with hetero-Ci-6alkyl selected from hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, Ci-6alkylamino-Ci-6alkyl, or N, Ndi- (Ci-6alkyl) -amino -Ci-6alkyl.

[000131] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1 -yl optionally substituted in position 5 with methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl , cyclopropyl, cyclopropylmethyl, trifluoromethyl, pentafluoro-ethyl, 1,1-difluoro-ethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, or dimethylamino-methyl.

[000132] In certain embodiments of formula I, R ¹ is [1,2,4] triazol-1 -yl optionally substituted in position 5 with methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl , cyclopropyl or cyclopropylmethyl.

[000133] In certain embodiments of formula I, R ² is phenyl substituted once or twice independently with halo or methyl.

[000134] In many embodiments of formula I, R ² is phenyl substituted in position 4 with methyl or halo and optionally substituted in positions 2 and 6 with halo.

[000135] In many embodiments of formula I, R ² is phenyl substituted in position 4 with methyl or halo and optionally substituted in position 2 with halo.

[000136] In certain embodiments of formula I, R ² is 4-methyl-phenyl, 2-fluoro4-methyl-phenyl, 2-chloro-4-fluoro-phenyl, 4-chloro-2-fluoro-phenyl, 2,4 -dichloro-phenyl, 2,4-difluoro-phenyl, or 2-chloro-4-methyl-phenyl.

[000137] In certain embodiments of formula I, R ² is 4-methyl-phenyl or 4-chloro-phenyl.

[000138] [000139] [000140] [000141] [000142] [000143] [000144] [000145]

In certain modalities of formula I In certain modalities of formula I In certain modalities of formula I In certain modalities of formula I In certain modalities of formula I In certain modalities of formula I

R ²

R ²

R ²

R ²

R ²

R ²

R ²

In many embodiments of formula I, it is 4-methyl-phenyl. is 2-fluoro-4-methyl-phenyl. is 2-chloro-4-fluoro-phenyl. is 4-chloro-2-fluoro-phenyl. is 2,4-dichloro-phenyl. is 2,4-difluoro-phenyl. is 2-chloro-4-methyl-phenyl. R ² is optional pyridinyl Petition 870180137880, of 10/04/2018, p. 11/34

22/98 replaced. Exemplary pyridinyl includes pyridin-2-yl, and pyridin-2-one-1-yl, each optionally substituted once, twice three times with any one of Ci-6alkyl, Ci-6alkyloxy, halo, Ci-6haloalkyl, hetero -Ci-6alkyl, C1-6alkylsulfonyl or cyano. Preferred pyridyl includes 4-methyl-pyridin-2-yl, 4-fluoro-pyridin-2-yl and 4-methyl-pyridin-2-one-1-yl.

[000146] In certain embodiments of formula I, R ² is pyridin 2-yl substituted with methyl or halo in position 5.

[000147] In certain embodiments of formula I, R ² is pyridin 2-yl substituted with methyl or halo in position 5 and optionally substituted with halo in position 3.

[000148] In certain embodiments of formula I, R ² is 5-methyl-pyridin-2-yl, 5chloro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 5-methyl-3-fluoro-pyridine -2-yl, 5-methyl-3chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-pyridin-2-yl.

[000149] In certain embodiments of formula I, R ² is 5-methyl-pyridin-2-yl.

[000150] In certain embodiments of formula I, R ² is 5-chloro-pyridin-2-yl.

[000151] In certain embodiments of formula I, R ² is 5-fluoro-pyridin-2-yl.

[000152] In certain embodiments of formula I, R ² is 5-methyl-3-fluoro-pyridin2-yl.

[000153] In certain embodiments of formula I, R ² is 5-methyl-3-chloro-pyridin2-yl.

[000154] In certain embodiments of formula I, R ² is 3,5-difluoro-pyridin-2ila.

[000155] In certain embodiments of formula I, R ² is 3,5-dichloro-pyridin-2yl.

[000156] In certain embodiments of formula I, R ² is optionally substituted pyridazinyl. In such embodiments R ² can be 6-chloro-pyridazinyl or 6methyl-pyridazinyl, preferably 6-chloro-pyridazinyl.

[000157] In certain embodiments of formula I, R ² is optionally substituted thiophenyl. R ² can be thiophen-2-yl optionally substituted with C1-6 alkyl or halo in such embodiments. Preferred thiophenyl includes 3-methyl-thiophen-2-yl, 5-methyl-thiophen-2-yl and 5-chloro-thiophen-2-yl.

[000158] In many modalities of formula I, R ⁶ is hydrogen. In certain

Petition 870180137880, of 10/04/2018, p. 11/35

23/98 modalities of formula I, R ⁶ can be methyl.

[000159] In many modalities of formula I, R ³ is hydrogen.

[000160] In certain modalities of formula I, R ⁴ is hydrogen.

[000161] In many embodiments of formula I, R ³ is Ci-6alkyl. A preferred C1-6 alkyl in such embodiments is methyl.

[000162] In many embodiments of formula I, R ⁴ is Ci-6alkyl. A preferred C1-6 alkyl in such embodiments is methyl.

[000163] In many embodiments of formula I, R ³ is hydrogen and R ⁴ is C1-6 alkyl, preferably methyl.

[000164] In certain modalities of formula I, R ³ and R ⁴ are hydrogen. [000165] In certain embodiments of formula I, R ³ and R ⁴ together with the atom to which they are attached can form a C3-6 carbocyclic ring.

[000166] In certain modalities of formula I, R ³ and R ⁴ together with the atom to which they are attached can form a cyclopropyl group.

[000167] In certain embodiments of formula I, R ⁴ and R ⁵ together with the atom to which they are attached form a C3-6 carbocyclic ring that is optionally substituted with hydroxy.

[000168] In certain modalities of formula I, R ⁴ and R ⁵ together with the atom to which they are attached form a cyclopropyl group.

[000169] In certain modalities of formula I, R ³ is hydrogen and R ⁴ and R ⁵ together with the atom to which they are attached form a cyclopropyl group. [000170] In certain embodiments of formula I, R ³ is hydrogen and R ⁴ and R ⁵ together with the atom to which they are attached form a cyclopentyl group optionally substituted with hydroxy.

[000171] In certain modalities of formula I, R ⁴ and R ⁵ together with the atom to which they are attached form a C4-6 heterocyclic ring containing one or two heteroatoms each independently selected from O, N and S. [000172] In certain modalities of formula I, R ⁴ and R ⁵ together with the atom to which they are attached form a piperidinyl group or oxetanyl ring group.

[000173] In certain embodiments of formula I, R ⁴ and R ⁵ together with the atom to which they are attached form a piperidin-3-yl group or a group

Petition 870180137880, of 10/04/2018, p. 36/114

24/98 oxetan-3-yl.

[000174] In certain modalities of formula I, R ³ , R ⁴ and R ⁵ together with the atom to which they are attached form a six-membered heteroaryl containing one or two nitrogen atoms, and which are optionally substituted with halo, amino or C1-6alkyl.

[000175] In certain modalities of formula I, R ³ , R ⁴ and R ⁵ together with the atom to which they are attached form a heteroaryl selected from 2oxo-1,2-dihydro-pyrimidinyl, pyridinyl, pyrimidinyl, pyridazinyl or pyridazinyl, each optionally substituted with methyl or amino.

[000176] In certain modalities of formula I, R ³ , R ⁴ and R ⁵ together with the atom to which they are attached form a heteroaryl selected from 2oxo-1,2-dihydro-pyrimid id η-4- i-la, 2-oxo-1,2-dihydro-pyri m id i η-4-la, 1-methyl-2oxo-1,2-dihydro-pyrimidin-4-yl, 6-methyl -pyridin-3-yl, pyridazin-4-yl, 6-aminopyridin-2-yl, 2-aminopyrimidin-4-yl or 2-amino-pyrimidin-3-yl.

[000177] In certain modalities of formula I, R ⁵ is: Ci-6alkyl; C1-6alkyloxy-C1-6alkyl; hydroxy-C1-6 alkyl; C1-6alkylsulfanyl-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; amino-C1-6alkyl; N-C1-6alkyl-amino-C1-6alkyl; N, N-di-C1-6 alkyl-amino-C1-6alkyl; C3-7Cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C1-6 alkyl.

[000178] In certain embodiments of formula I, R ⁵ is halo-substituted N-C1-6 alkylamino-C1-6 alkyl.

[000179] In certain embodiments of formula I, R ⁵ is: C1-6alkyloxy-C1-6 alkyl; hydroxy-C1-6 alkyl; heteroaryl, or heterocyclyl-C1-6 alkyl.

[000180] In certain embodiments of formula I, R ⁵ is C1-6alkyloxy-C1-6 alkyl. A preferred C1-6alkyloxy-C1-6alkyl is methoxymethyl.

[000181] In certain embodiments of formula I, R ⁵ is hydroxy-C1-6 alkyl. A preferred hydroxy-C1-6 alkyl is hydroxymethyl.

[000182] In certain modalities of formula I, R ⁵ is heteroaryl.

[000183] In certain embodiments where R ⁵ is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl, 3-oxo-2,3-di-2,3-di hydroisoxazolyl, tetrazolyl, imidazo [2,1-bjtiazolyl, imidazo [1,2-a] pyridinyl, imidazo

Petition 870180137880, of 10/04/2018, p. 37/114

25/98 [4,5-b] pyridinyl, and benzimidazolyl, each of which can optionally be substituted once, twice, or three times with a group or groups independently selected from C1-6alkyl, C1-6alkoxy, C1-6alkoxy-C1- 6alkyl, haloCi-6alkyl, halo, amino, N-C1-6alkyl-amino, or N, N-di- (C1-6alkyl) -amino. More preferably, such a heteroaryl can be optionally substituted once or twice with a group or groups independently selected from methyl, ethyl, n-propyl, fluorine, chlorine, trifluoromethyl, amino, methylamino or dimethylamino.

[000184] In certain embodiments where R ⁵ is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl or thiazolyl, each of which may optionally be substituted once or twice with a group or groups independently selected from methyl, ethyl , n-propyl, fluorine, chlorine, amino, methylamino or dimethylamino.

[000185] In certain embodiments where R ⁵ is heteroaryl, such heteroaryl may be pyridinyl, pyrimidinyl, or pyrazinyl, each of which may optionally be substituted once or twice with a group or groups independently selected from methyl, fluorine, chlorine, amino, methylamino or dimethylamino.

[000186] In certain embodiments of formula I, where R ⁵ is heteroaryl, such heteroaryl may be thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, oxazol2-yl, pyrimidine- 2-yl, pyridazin-4-yl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, imidazol1-yl, pyrazol-1-yl, 3,5-dimethyl-pyrazol-1-yl, 2- methyl-thiazol-4-yl, 3- (2-chlorophenyl) - [1,2,4] -oxadiazol-5-yl, 3- (pyridin-4-yl) - [1,2,4] -oxadiazole- 5-yl, pyridazin-3yl, 2-methyl-pyrazol-3-yl, thiazol-5-yl, 1-methyl-imidazol-2-yl, 6-chloro-pyrimidin-4yl, 4-ethyl- [1,2 , 4] -triazol-3-yl, 1,3,5-trimethyl-pyrazol-4-yl, 1,5-dimethyl-pyrazol-4yl, 1,3-dimethyl-pyrazol-4-yl, 3- (2 -methoxy-ethyl) - [1,2,4] -oxadiazol-5-yl, 3- (pyridin3-yl- [1,2,4] -oxadiazol-5-yl, tetrazol-5-yl, pyrazol-3 -yl, 4-amino-2-methyl-pyrimidin-5-yl, 2-amino-pyrimidin-4-yl, 6-methoxy-pyridazin-3-yl, 3-oxo-2,3-dihydroisoxazole-5 -yl, 3-methyl-thiophen-2-yl, 5-methyl- [1,3,4] -oxadiazol-2-yl, 4-methyl-issoxazol-3-yl, 3-trifluoromethyl-pyrazol-1-yl , 1-methyl-pyrazol-3-yl, 3-methyl -pyrazol-1yl, 5-methyl-3-trifluoromethyl-pyrazol-1-yl, 5-cyclopropyl-3-trifluoromethyl-pyrazol-1-yl, imidazo [2,1-b] -thiazol-6-yl, thiazole-4 -ila, 2-propyl-pyrazol-3-yl, 2-ethyl-pyrazole Petition 870180137880, of 10/04/2018, p. 11/38

26/98

3-yl, 5-amino-pyridazin-2-yl, 3-amino-pyridazin-2-yl, 3-chloro-pyridazin-2-yl, 2 amino-pyrimidin-5-yl, 1-methyl-imidazole-4 -yl, 6-amino-pyridin-3-yl, 6-amino pyridazin-2-yl, 2-amino-pyridin-4-yl, 2-dimethylamino-pyrimidin-5-yl, 6-amino pyridin-2-yl , 2-methylamino-pyridin-4-yl, 2-dimethylamino-pyridin4-yl, 3-methyl-2 dimethylamino-pyridin-4-yl, pyrimidin-5-yl, 2-methyl-pyridin-4-yl, 6- methylamino pyridin-3-yl, 6-dimethylamino-pyridin-3-yl, 6-methylamino-pyrimidin-4-yl, 6-dime tilamino-pyridin-3-yl, 6-methylamino-pyridin-3-yl, 2- methylamino-pyrimidin-5-yl, 6 methyl-pyridin-3-yl, 4-methyl-thiazol-2-yl, 2,6-dimethyl-pyridin-3-yl, imidazo [1,2 a] pyridin-2- ila, 6-methyl-pyridin-2-yl, 1-ethyl-pyrazol-3-yl, 3-methyl-pyridin-2-yl, 4 methyl-thiazol-5-yl, 1-ethyl-imidazol-2-yl , 1-methyl-pyrazol-4-yl, imidazo [4,5-b] pyridin-2-yl, 3,5-difluoro-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 1, 5-dimethyl-pyrazol-3-yl, 5-methyl-pyridin-2-yl, 6-trifluoromethyl-pyridin-3-yl, 5-methyl-isoxazol-3-yl, 5 methyl-imidazol-2-yl, 5-methoxy-benzimidazol-2-yl, [1,2,4] triazol-3-yl, 6-methyl pyridazin-3-yl, 1-methyl-6-oxo-1, 6-dihydro-pyridin-3-yl or 8-methyl-imidazo [1,2a] pyridin-2-yl.

[000187] In certain embodiments of formula I, R ⁵ is heterocyclyl-C1-6 alkyl. [000188] In embodiments where R ⁵ is heterocyclyl-C1-6alkyl, such heterocyclyl-C1-6alkyl may be heterocyclyl-methyl such as morpholinomethyl, piperi-dinylmethyl, piperazinyl-methyl, thiomorpholinylmethyl, pyrrolidinylmethyl, or azethyl dinylmethyl, to portion heterocyclyl of each of these can optionally be substituted once or twice with a group or groups independently selected from methyl, methoxy, halo, methanesulfonyl, oxo or aceyl.

[000189] In embodiments where R ⁵ is heterocyclyl-methyl, such heterocyclyl may be morpholin-4-yl-methyl, 4-methanesulfonyl-piperazin-1-yl-methyl, 4 acetyl-piperazin-1-yl-methyl, piperidin -1-yl, thiomorfolin-4-yl-methyl, 4-methyl-pipe razin-1-yl-methyl, 3-oxo-piperazin-1-yl-methyl, 3-methoxy-piperidin-1-yl-methyl, 4 methoxy-piperidin-1-yl-methyl, 4-hydroxy-piperidin-1-yl-methyl, 1-oxo-thiomorfolin-4 yl-methyl, 3-hydroxy-pyrrolidin-1-yl-methyl, azetidin-3- ylmethyl, 4-methanesulfonyl piperidin-1-yl-methyl, 4-fluoro-piperidin1-yl-methyl, 4-acetyl-3-methyl-piperazin-1 yl-methyl, 4-acetyl-3,5-dimethyl- piperazin-1-yl-methyl, 2,6-dimethyl-morphol-4-yl methyl, 4, 4-difluoro-piperidin1-yl-methyl, 3-fluoro-piperidin1 -yl-methyl, 4-methyl-4

Petition 870180137880, of 10/04/2018, p. 39/114

27/98 hydroxy-piperidiη 1-yl-methyl, or 3-fluoro-4-methoxy-piperidin1-yl-methyl.

[000190] In certain embodiments of formula I, R ⁵ is hydroxymethyl, methoxymethyl, pyrazin-2-yl or 5-methyl-pyrazin-2-yl.

[000191] In certain embodiments of formula I, R ⁵ is hydroxymethyl, methoxymethyl, pyrazin-2-yl, 5-methyl-pyrazin-2-yl, 6-methyl-pyridazin-3-yl, or 1-methyl-6oxo- 1,6-dihydro-pyridi η-3-ia.

[000192] In certain embodiments of formula I, R ⁵ is hydroxymethyl.

[000193] In certain modalities of formula I, R ⁵ is methoxymethyl.

[000194] In certain embodiments of formula I, R ⁵ is pyrazin-2-yl.

[000195] In certain embodiments of formula I, R ⁵ is 5-methyl-pyrazin-2-yl.

[000196] In certain embodiments of formula I, R ⁵ is 1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl.

[000197] In certain embodiments of formula I, R ⁵ is 6-methyl-pyridazin-3-yl.

[000198] In certain modalities of formula I, R ⁶ , R ⁷ and R ⁸ are hydrogen.

[000199] In certain modalities of formula I, R ⁷ and R ⁸ are hydrogen.

[000200] In certain modalities of formula I, one of R ⁷ and R ⁸ is halo or Ci4 alkoxy and the other is hydrogen.

[000201] In certain modalities of formula I, both R ⁷ and R ⁸ are halo or Ci-4 alkoxy.

[000202] In certain modalities of formula I, one of R ⁷ and R ⁸ is fluorine, chlorine or methoxy, and the other is hydrogen.

[000203] In certain modalities of formula I, R ⁷ and R ⁸ each independently is fluorine, chlorine or methoxy.

[000204] In certain modalities of formula I, R ⁷ and R ⁸ are fluoro.

[000205] In certain modalities of formula I, one of R ⁷ and R ⁸ is fluoro and the other is hydrogen.

[000206] In certain modalities of formula I, one of R ⁷ and R ⁸ is chlorine and the other is hydrogen.

[000207] In certain modalities of formula I, one of R ⁷ and R ⁸ is methoxy and the other is hydrogen.

[000208] In certain modalities of formula I, R ⁶ is halo.

[000209] In certain modalities of formula I, R ⁶ is fluoro.

Petition 870180137880, of 10/04/2018, p. 40/114

28/98 [000210] In certain modalities of formula I:

[000211] R ¹ is [1,2,4] triazol-1-yl optionally substituted in position 5 with Ci-6alkyl, halo-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, hydroxy-Ci-6 alkyl, Ci -6alquilamino 6alquila -alkyl, N, N-di- (Ci-6alquil) -amino-Ci-6alquila, C3-6cicloalquila, or C ₃ -C -6Cicloalquil-6alquila;

[000212] R ² is 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluorophenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl; or 2-chloro4-methyl-phenyl;

[000213] R ³ is hydrogen;

[000214] R ⁴ is: hydrogen; or methyl; and [000215] R ⁵ is C1-6 alkyl; C1-6alkyloxy-C1-6alkyl; hydroxy-C1-6 alkyl; C1-6 alkylsulfanyl-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; amino-C1-6alkyl; N-C1-6 alkyl-amino-C1-6alkyl; N, N-di-C1-6alkyl-amino-C1-6alkyl; C ₃ -7Cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C1-6 alkyl. [000216] In certain modalities of formula I:

[000217] R ¹ is [1,2,4] triazol-1-yl optionally substituted in position 5 with C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, C1- Ci-6-alkylamino 6alquila, N, N-di- (Ci-6alquil) -amino-Ci-6alquila, _C3 -6-cycloalkyl or _C3-C -6Cicloalquil 6alquila;

[000218] R ² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2yl, 5-methyl-3-fluoro-pyridin-2-yl, 5- methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin-2-yl or 3,5-dichloro-pyridin-2-yl;

[000219] R ³ is hydrogen;

[000220] R ⁴ is hydrogen; or methyl; and [000221] R ⁵ is C1-6 alkyl; C1-6alkyloxy-C1-6alkyl; hydroxy-C1-6 alkyl; C1-6 alkylsulfanyl-C1-6alkyl; C1-6alkylsulfonyl-C1-6alkyl; amino-C1-6alkyl; N-C1-6 alkyl-amino-C1-6alkyl; N, N-di-C1-6alkyl-amino-C1-6alkyl; C ₃ -7Cycloalkyl; optionally substituted phenyl; heteroaryl, or heterocyclyl-C1-6 alkyl. [000222] In certain modalities of formula I:

[000223] ^R1 is [1,2,4] triazol-1-ila optionally substituted at position 5 with C-6alquila, halo-Ci-6alquila, C-C 6alcóxi 6alquila, hydroxy-Ci-6alquila, C ₃ 6-cycloalkyl, or C ₃ -6Cycloalkyl-C1-6alkyl;

Petition 870180137880, of 10/04/2018, p. 41/114

29/98 [000224] R ² is 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl;

4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl; or 2-chloro-4methyl-phenyl;

[000225] R ³ is hydrogen;

[000226] R ⁴ is hydrogen; or methyl; and [000227] R ⁵ is hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl; piperidin-1-yl methyl optionally substituted in position 4 with methyl, methanesulfonyl or acetyl; 1,1, -dioxo-thiomorpholin-1-yl; piperidin-1-yl-methyl optionally substituted once or twice with a group or groups selected independently from methyl, methoxy or halo; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl each can optionally be replaced once or twice with a group or groups selected independently of methyl, methylamino, dimethylamino and halo.

[000228] In certain modalities of formula I:

[000229] R ¹ is [1,2,4] triazol-1-yl optionally substituted in position 5 with C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, C1- 6 C1-6 alkylamino, C3-6-cycloalkyl, or C3-6Cycloalkyl-C1-6alkyl; [000230] R ² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2yl, 5-methyl-3-fluoro-pyridin-2-yl, 5- methyl-3-chloro-pyridin-2-yl, 3,5-difluoropyridin-2-yl or 3,5-dichloro-pyridin-2-yl;

[000231] R ³ is hydrogen;

[000232] R ⁴ is hydrogen; or methyl; and [000233] R ⁵ is hydroxymethyl; methoxymethyl; morpholin-4-ylmethyl; piperidin-1-yl methyl optionally substituted in position 4 with methyl, methanesulfonyl or acetyl; 1,1, -dioxo-thiomorpholin-1-yl; piperidin-1-yl optionally substituted once or twice with a group or groups selected independently from methyl, methoxy or halo; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; pyrazolyl; or thiazolyl; wherein the pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and thiazolyl each can optionally be replaced once or twice with a group or groups selected independently of methyl, methylamino, dimethylamino and halo.

Petition 870180137880, of 10/04/2018, p. 42/114

30/98 [000234] In certain modalities of formula I:

[000235] ^R1 is [1,2,4] triazol-1-ila optionally substituted at position 5 with C-6alquila, halo-Ci-6alquila, C-C 6alcóxi 6alquila, hydroxy-Ci-6alquila, C ₃ 6-cycloalkyl, or C ₃ -6Cycloalkyl-C1-6alkyl;

[000236] R ² is 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl; or 2-chloro-4methyl-phenyl;

[000237] R ³ is hydrogen; and [000238] R ⁴ and R ⁵ together form a cyclopropyl group.

[000239] In certain modalities of formula I:

[000240] R ¹ is [1,2,4] triazol-1-yl optionally substituted in position 5 with C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, C1- Ci-6-alkylamino 6alquila, _C3 -6-cycloalkyl or _C3-C -6Cicloalquil 6alquila; [000241] R ² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2yl, 5-methyl-3-fluoro-pyridin-2-yl, 5- methyl-3-chloro-pyridin-2-yl, 3,5-difluoropyridin-2-yl or 3,5-dichloro-pyridin-2-yl;

[000242] R ³ is hydrogen; and [000243] R ⁴ and R ⁵ together form a cyclopropyl group.

[000244] In certain modalities of formula I:

[000245] R ¹ is [1,2,4] triazol-1-yl optionally substituted in position 5 with C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, C1- Ci-6-alkylamino 6alquila, N, N-di- (Ci-6alquil) -amino-Ci-6alquila, _C3 -6-cycloalkyl or _C3-C -6Cicloalquil 6alquila;

[000246] R ² is 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl; or 2-chloro-4methyl-phenyl;

[000247] [000248] [000249]

R ³ is hydrogen;

R ⁴ is methyl; and

R ⁵ is methoxymethyl, hydroxymethyl, 5-methyl-pyrazin-2-yl or pyrazin2-yl.

[000250] In certain modalities of formula I:

[000251] R ¹ is [1,2,4] triazole-1-yl optionally substituted in position 5

Petition 870180137880, of 10/04/2018, p. 43/114

31/98 with Ci-6alkyl, halo-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, hydroxy-Ci-6alkyl, Ci-6alkylamino-Ci-6alkyl, N, N-di- (Ci-6alkyl) -amino- C1-6alkyl, C3-6-cycloalkyl, or C3-6Cycloalkyl-C1-6alkyl;

[000252] R ² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2yl, 5-methyl-3-fluoro-pyridin-2-yl, 5- methyl-3-chloro-pyridin-2-yl, 3,5-difluoro-pyridin -2-yl or 3,5-dichloro-pyridin-2-yl;

[000253] R ³ is hydrogen;

[000254] R ⁴ is methyl; and [000255] R ⁵ is methoxymethyl, hydroxymethyl, 5-methyl-pyrazin-2-yl or pyrazin2-yl.

[000256] In certain modalities of formula I:

[000257] R ¹ is [1,2,4] triazol-1-yl optionally substituted in position 5 with C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, C1- Ci-6-alkylamino 6alquila, N, N-di- (Ci-6alquil) -amino-Ci-6alquila, _C3 -6-cycloalkyl or _C3-C -6Cicloalquil 6alquila;

[000258] R ² is 4-methyl-phenyl; 2-fluoro-4-methyl-phenyl; 2-chloro-4-fluoro-phenyl; 4-chloro-2-fluoro-phenyl; 2,4-dichloro-phenyl; 2,4-difluoro-phenyl; or 2-chloro-4methyl-phenyl;

[000259] R ³ and R ⁴ are hydrogen; and [000260] R ⁵ is 5-methyl-pyrazin-2-yl.

[000261] In certain modalities of formula I:

[000262] R ¹ is [1,2,4] triazol-1-yl optionally substituted at position 5 with C1-6alkyl, halo-C1-6alkyl, C1-6alkoxy-C1-6alkyl, hydroxy-C1-6alkyl, C1- Ci-6-alkylamino 6alquila, N, N-di- (Ci-6alquil) -amino-Ci-6alquila, _C3 -6-cycloalkyl or _C3-C -6Cicloalquil 6alquila;

[000263] R ² is 5-methyl-pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-fluoro-pyridin-2yl, 5-methyl-3-fluoro-pyridin-2-yl, 5- methyl-3-chloro-pyridin-2-yl, 3,5-difluoropyridin-2-yl or 3,5-dichloro-pyridin-2-yl;

[000264] R ³ and R ⁴ are hydrogen; and [000265] R ⁵ is 5-methyl-pyridazin-2-yl.

[000266] In certain modalities of formula I, R ¹ is a group of the formula

A or B;

Petition 870180137880, of 10/04/2018, p. 44/114

32/98

R

THE;

B;

where R ^c and R ^d each independently is hydrogen; C1-6alkyl; C1-6 alkoxy; C1-6 alkylsulfonyl; phenyl; amino; N-C1-6 alkyl-amino; N, N-di-C1-6alkylamino halo-C1-6alkyl; halo-C1-6 alkoxy; hetero-C1-6alkyl; C3-6-cycloalkyl; C3-6Cycloalkyl-C1-6alkyl; aminocarbonyl; heterocyclylcarbonyl; C1-6 alkoxycarbonyl; or cyan; or R ^c and R ^d together with the atoms to which they are attached can form a phenyl, pyridinyl or pyrimidinyl group, each optionally substituted.

[000267] In certain modalities of formula I, R ¹ is a group of formula A.

[000268] In certain modalities of formula I, R ¹ is a group of formula A1:

N — N

A1 where R ^a and R ^b are as defined here.

[000269] In certain modalities of formula I, R ¹ is a group of formula A2:

Νχ, N

R ^d

A2 where R ^a and R ^b are as defined here.

[000270] In certain modalities of formula I, R ¹ is a group of formula A3:

N

R ^cJ L_; Ã ^RÍ

A3 where R ^a and R ^b are as defined here.

[000271] In certain modalities of formula I, R ¹ is a group of the formula

Petition 870180137880, of 10/04/2018, p. 45/114

33/98

Β.

[000272] In certain modalities of formula I, R ¹ is a group of formula B1:

where R ^a and R ^b are as defined here.

[000273] In certain modalities of formula I, R ¹ is a group of formula B2:

/ ^N x.

r ^c 4 ^ R ^d

B2 where R ^a and R ^b are as defined here.

[000274] In certain modalities of formula I, R ¹ is a group of formula B3:

N — N

B3 where R ^a and R ^b are as defined here.

[000275] In certain modalities of formula I, R ^c is hydrogen and R ^d is: hydrogen; C1-6alkyl; C1-6 alkoxy; C1-6 alkylsulfonyl; amino; N-C1-6 alkylamino; N, N-di-C1-6alkyl-amino halo-C1-6alkyl; halo-C1-6 alkoxy; hetero-C1-6alkyl; C3-6-cycloalkyl; C3-6Cycloalkyl-C1-6alkyl; aminocarbonyl; heterocyclylcarbonyl; C1-6 alkoxycarbonyl; or cyan.

[000276] In modalities of formula I in which R ^c or R ^d is hetero-C1-6 alkyl, such hetero-C1-6 alkyl may be selected from hydroxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkyl 6alkylamino-C1-6alkyl, and N, N-di- (C1-6alkyl) -amino-C1-6 alkyl.

[000277] In certain modalities of formula I, R ^c is hydrogen and R ^d is methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, phenyl, trifluoromethyl, difluoromethyl, fluoromethyl,

Petition 870180137880, of 10/04/2018, p. 46/114

34/98 pentafluoro-ethyl, 1,1-difluoro-ethyl, 2,2-difluoroethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, isopropoxy, dimethylamino , azetidin2-yl, 1-methyl-azetidin-2-yl, 1-dimethylamino-ethyl or dimethylamino-methyl. [000278] In certain embodiments of formula I, R ^c is hydrogen and R ^d is C1-6 alkyl or halo-C1-6 alkyl.

[000279] In certain embodiments of formula I, R ^c is hydrogen and R ^d is C1-6 alkyl.

[000280] In certain embodiments of formula I, R ^c is hydrogen and R ^d is C1-6 alkoxy.

[000281] In certain embodiments of formula I, R ^c is hydrogen and R ^d is C1-6 alkylsulfonyl.

[000282] In certain modalities of formula I, R ^c is hydrogen and R ^d is amino.

[000283] In certain embodiments of formula I, R ^c is hydrogen and R ^d is NCi-6alkyl-amino.

[000284] In certain modalities of formula I, R ^c is hydrogen and R ^d is N, Ndi-Ci-6-alkyl-amino.

[000285] In certain embodiments of formula I, R ^c is hydrogen and R ^d is halo-C1-6 alkyl.

[000286] In certain modalities of formula I, R ^c is hydrogen and R ^d is halo-C1-6 alkoxy.

[000287] In certain modalities of formula I, R ^c is hydrogen and R ^d is hetero-C1-6alkyl.

[000288] In certain modalities of formula I, R ^c is hydrogen and R ^d is C3-6cycloalkyl.

[000289] In certain embodiments of formula I, R ^c is hydrogen and R ^d is C3-6 cycloalkyl-C1-6alkyl.

[000290] In certain modalities of formula I, R ^c is hydrogen and R ^d is aminocarbonyl.

[000291] In certain modalities of formula I, R ^c is hydrogen and R ^d is heterocyclylcarbonyl.

[000292] In certain modalities of formula I, R ^c is hydrogen and R ^d is C1-6

Petition 870180137880, of 10/04/2018, p. 47/114

35/98 alkoxycarbonyl.

[000293] In certain modalities of formula I, R ^c is hydrogen and R ^d is cyan.

[000294] In certain modalities of formula I, R ^b is hydrogen and R ^d is methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclopropylmethyl, trifluoromethyl, pentafluoro-ethyl, 1, 1-difluoro-ethyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-1-methyl-ethyl, 1-hydroxy-ethyl, or dimethylaminomethyl.

[000295] In certain modalities of formula I, R ^c is hydrogen and R ^d is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl or cyclopropylmethyl.

[000296] In certain modalities of formula I, R ^c and R ^d together with the atoms to which they are attached form optionally substituted phenyl. [000297] In certain modalities of formula I, R ^c and R ^d together with the atoms to which they are attached form optionally substituted pyridinyl. [000298] In certain modalities of formula I, R ^c and R ^d together with the atoms to which they are attached form optionally substituted pyrimidinyl.

[000299] Optionally substituted triazolyl as used herein includes triazolyl which optionally has a 6-membered aromatic fused or nitrogen containing heteroaryl ring. Thus, optionally substituted triazolyl includes benzotriazolyl, [1,2,4] triazolo [4,3-a] pyridinyl, [1,2,4] triazolo [1,5-a] pyridinyl, and aza-substituted derivatives thereof . Consequently, in certain modalities of formula I where R ¹ is of formula A and R ^c and R ^d together with the atoms to which they are attached form a phenyl, pyridinyl or pyrimidinyl group, then R ¹ can be represented by a group of formula A4:

R ^f

A4 where X ¹ and X ² each independently is CR ^f or N, and R ^e and R ^f each independently is hydrogen, C1-6 alkyl, C1-6 alkyloxy, or halo. In many

Petition 870180137880, of 10/04/2018, p. 48/114

36/98 such modalities R ^c and R ^d together with the atoms to which they are attached form a pyridinyl group so that X ¹ and X ² are CH.

[000300] In certain modalities of formula I where R ¹ is of formula B and R ^c and R ^d together with the atoms to which they are attached form a phenyl, pyridinyl or pyrimidinyl group, then R ¹ can be represented by a group of formula B4:

wherein X ¹ and X ² each independently is CR ^f or N, and R ^e and R ^f each independently is hydrogen, C1-6 alkyl, C1-6 alkyloxy, or halo. In many such modalities R ^a and R ^b together with the atoms to which they are attached form a phenyl group so that X ¹ and X ² are CH.

[000301] In many embodiments of formula I, R ³ is hydrogen and R ⁴ is C1-6 alkyl, preferably methyl.

[000302] In certain embodiments of formula I, R ² is 4-methyl-phenyl, 4-chlorophenyl or 2-fluoro-4-methyl-phenyl, and R ³ is hydrogen.

[000303] In certain embodiments of formula I, R ² is 4-methyl-phenyl, 4-chlorophenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, and R ⁴ is methyl.

[000304] In certain embodiments of formula I, R ² is 4-methyl-phenyl, 4-chlorophenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, and R ⁶ is hydrogen.

[000305] In certain modalities of formula I, R ² is 4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is:

[000306] Ci-6alkyl selected from methyl, ethyl, propyl, isopropyl, nbutyl, isobutyl, tert-butyl, n-pentyl and isopentyl;

[000307] hetero-C1-6alkyl selected from C1-6alkyloxy-C1-6alkyl, hydroxy-C1-6alkyl, C1-6alkylsulfanyl-C1-6alkyl, C1-6alkyl-sulfinyl-C1-6alkyl, C1-6alkyl-sulfonyl-Ci- 6alkyl, amino-C1-6alkyl, N-C1-6alkylamino-C1-6alkyl, N, Ndi-C1-6alkylamino-C1-6alkyl and hydroxy-C1-6alkyloxy;

[000308] C3-7 Cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted;

Petition 870180137880, of 10/04/2018, p. 11/4

37/98 [000309] aryl selected from optionally substituted phenyl and optionally substituted naphthyl;

[000310] heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, isoxazolyl and isothiazolyl, each optionally substituted;

[000311] heterocyclyl selected from piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, 2-oxa-8-aza-spiro [4.5] decan- 8-yl, 2-oxa-5-aza-bicyclo [2.2.1] heptan-5-ila, and 3-oxa-8-aza-bicyclo [3.2.1] octan-8-ila, each optionally substituted;

[000312] C3-7Cycloalkyl-C1-6alkyl selected from cyclopropyl-C1-6alkyl, cyclobutyl-C1-6alkyl, cyclopentyl-C1-6alkyl and cyclohexyl-C1-6alkyl, the cycloalkyl portion of each being optionally substituted;

[000313] aryl-C1-6alkyl selected from phenyl-C1-6alkyl and naphthyl-C1-6alkyl, the aryl portion of each being optionally substituted;

[000314] heteroaryl-Ci-6alkyl selected from pyridinyl-Ci-6alkyl, pyrimidinyl-Ci-6alkyl, pyridazinyl-Ci-6alkyl, pyrazinyl-Ci-6alkyl, furanyl-Ci-6alkyl, thienyl-Ci-6alkyl, pyrrolyl-Cyl 6alkyl, oxazolyl-C1-6alkyl, thiazolyl-C1-6alkyl, imidazolyl-C1-6alkyl, isoxazolyl-C1-6alkyl and isothiazolyl-C1-6alkyl, the heteroaryl portion of each being optionally substituted;

[000315] heterocyclyl-C1-6alkyl selected from piperdinyl-C1-6alkyl, piperazinyl-C1-6alkyl, morpholinyl-C1-6alkyl, thiomorpholinyl-C1-6alkyl, 1-oxo-thiomorpholinyl-C1-6alkyl, 1,1-dioxo thiomorpholinyl-C1-6alkyl, pyranyl-C1-6alkyl, pyrrolidinyl-C1-6alkyl, tetrahydrofuranyl-C1-6alkyl, 2-oxa-8-aza-spiro [4.5] decan8-iI - C1 -6alkyl, 2-oxa -5-aza-bicyclo [2.2.1] heptan-5-yl-Ci-6alkyl, 3-oxa-8-azabicyclo [3.2.1] octan-8-yl - Ci-6alkyl, the heterocyclyl portion of each optionally being replaced;

[000316] aryloxy-C1-6alkyl selected from phenoxy-C1-6alkyl and naphthyloxy-C1-6 alkyl, the aryl portion of each being optionally substituted; or [000317] -C (O) -R ⁸ or -CH2-C (O) -R ⁸ where R ⁸ is as defined here.

[000318] In certain embodiments of formula I, R ² is 4-methyl-phenyl, 4-chlorophenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen,

Petition 870180137880, of 10/04/2018, p. 50/114

38/98 and R ⁵ is C1-6alkoxy-C1-6alkyl; hydroxy-C1-6 alkyl; morpholin-4-yl-C1-6alkyl; pyrazinyl; or piperazin-1-yl-C1-6alkyl wherein the piperazinyl moiety is optionally substituted in position 4 with C1-6alkyl, C1-6alkylcarbonyl or C1-6 alkylsulfonyl.

[000319] In certain embodiments of formula I, R ² is 4-methyl-phenyl, 4-chlorophenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is methoxymethyl; hydroxymethyl; morfolin-4-yl-methyl; pyrazin-2-yl; or 4 methanesulfonyl-piperazin-1-yl.

[000320] In certain embodiments of formula I, R ¹ is a group of formula A, R ² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is C1-6alkoxy-C1-6alkyl; hydroxy-C1-6 alkyl; morpholin-4-yl-C1-6alkyl; pyrazinyl; or piperazin-1-yl-C1-6alkyl wherein the piperazinyl moiety is optionally substituted in position 4 with C1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl.

[000321] In certain modalities of formula I, R ¹ is a group of the formula

A, R ² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is methoxymethyl; hydroxymethyl; morfolin4-yl-methyl; pyrazin-2-yl; or 4-methanesulfonyl-piperazin-1-yl.

[000322] In certain modalities of formula I, R ¹ is a group of the formula

B, R ² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is Ci-6 alkoxy- C1-6alkyl; hydroxy-C1-6 alkyl; morpholin-4-yl-C1-6alkyl; pyrazinyl; or piperazin-1-yl-C1-6alkyl wherein the piperazinyl moiety is optionally substituted in position 4 with C1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl.

[000323] In certain embodiments of formula I, R ¹ is a group of formula B, R ² is 4-methyl-phenyl, 4-chloro-phenyl or 2-fluoro-4-methyl-phenyl, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is methoxymethyl; hydroxymethyl; morfolin4-yl-methyl; pyrazin-2-yl; or 4-methanesulfonyl-piperazin-1-yl.

[000324] In certain embodiments of formula I, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, and R ³ is hydrogen.

[000325] In certain embodiments of formula I, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, and R ⁴ is methyl.

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39/98 [000326] In certain embodiments of formula I, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, and R ⁶ is hydrogen.

[000327] In certain embodiments of formula I, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is:

[000328] Ci-6alkyl selected from methyl, ethyl, propyl, isopropyl, nbutyl, isobutyl, tert-butyl, n-pentyl and isopentyl;

[000329] hetero-C1-6alkyl selected from C1-6alkyloxy-C1-6alkyl, hydroxy-C1-6alkyl, C1-6alkylsulfanyl-C1-6alkyl, C1-6alkyl-sulfinyl-C1-6alkyl, C1-6alkyl-sulfonyl-Ci- 6alkyl, amino-C1-6alkyl, N-C1-6alkylamino-C1-6alkyl, N, Ndi-C1-6alkylamino-C1-6alkyl and hydroxy-C1-6alkyloxy;

[000330] C3-7 Cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each optionally substituted;

[000331] aryl selected from optionally substituted phenyl and optionally substituted naphthyl;

[000332] heteroaryl selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, isoxazolyl and isothiazolyl, each optionally substituted;

[000333] heterocyclyl selected from piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, 2-oxa-8-aza-spiro [4.5] decan- 8-yl, 2-oxa-5-aza-bicyclo [2.2.1] heptan-5-ila, and 3-oxa-8-aza-bicyclo [3.2.1] octan-8-ila, each optionally substituted;

[000334] C3-7Cycloalkyl-C1-6alkyl selected from cyclopropyl-C1-6alkyl, cyclobutyl-C1-6alkyl, cyclopentyl-C1-6alkyl and cyclohexyl-C1-6alkyl, the cycloalkyl portion of each being optionally substituted;

[000335] aryl-C1-6alkyl selected from phenyl-C1-6alkyl and naphthyl-C1-6alkyl, the aryl portion of each being optionally substituted;

[000336] heteroaryl-Ci-6alkyl selected from pyridinyl-Ci-6alkyl, pyrimidinyl-Ci-6alkyl, pyridazinyl-Ci-6alkyl, pyrazinyl-Ci-6alkyl, furanyl-Ci-6alkyl, thienyl-Ci-6alkyl, pyrrolyl-Ci- 6alkyl, oxazolyl-C1-6alkyl, thiazolyl-C1-6alkyl,

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40/98 imidazolyl-C1-6alkyl, isoxazolyl-C1-6alkyl and isothiazolyl-C1-6alkyl, the heteroaryl portion of each being optionally substituted;

[000337] heterocyclyl-C1-6alkyl selected from piperdinyl-C1-6alkyl, piperazinyl-C1-6alkyl, morpholinyl-C1-6alkyl, thiomorpholinyl-C1-6alkyl, 1-oxo-thiomorpholinyl-C1-6alkyl, 1,1-dioxo- thiomorpholinyl-C1-6alkyl, pyranyl-C1-6alkyl, pyrrolidinyl-C1-6alkyl, tetrahydrofuranyl-C1-6alkyl, 2-oxa-8-aza-spiro [4.5] decan8-i I - C1 -6 here, 2 -oxa-5-aza-bicyclo [2.2.1] heptan-5-i I-Ci -6alkyl, 3-oxa-8aza-bicyclo [3.2.1] octan-8-yl - Ci-6alkyl, the portion heterocyclyl of each being optionally substituted;

[000338] aryloxy-C1-6alkyl selected from phenoxy-C1-6alkyl and naphthyloxy-C1-6 alkyl, the aryl portion of each being optionally substituted; or [000339] -C (O) -R ⁸ or -CH2-C (O) -R ⁸ where R ⁸ is as defined here.

[000340] In certain embodiments of formula I, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is Ci-6 alkoxy- C1-6alkyl; hydroxy-C1-6 alkyl; morpholin-4-yl-C1-6alkyl; pyrazinyl; or piperazin-1-yl-C1-6alkyl wherein the piperazinyl moiety is optionally substituted in position 4 with C1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl.

[000341] In certain embodiments of formula I, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is methoxymethyl; hydroxymethyl; morfolin-4-yl-methyl; pyrazin-2-yl; or 4 methanesulfonyl-piperazin-1-yl.

[000342] In certain embodiments of formula I, R ¹ is a group of formula A, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen , and R ⁵ is C1-6alkoxy-C1-6alkyl; hydroxy-C1-6 alkyl; morpholin-4-yl-C1-6alkyl; pyrazinyl; or piperazin-1-yl-C1-6alkyl wherein the piperazinyl moiety is optionally substituted in position 4 with C1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl.

[000343] In certain modalities of formula I, R ¹ is a group of the formula

A, R ² is pyridin-2-yl substituted at position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is methoxymethyl; hydroxymethyl; morfolin-4-yl-methyl; pyrazin-2-yl; or 4-methanesulfonyl-piperazin-1-yl.

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41/98 [000344] In certain embodiments of formula I, R ¹ is a group of formula B, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen, and R ⁵ is C1-6alkoxy-C1-6alkyl; hydroxy-C1-6 alkyl; morpholin-4-yl-C1-6alkyl; pyrazinyl; or piperazin-1-yl-C1-6alkyl wherein the piperazinyl moiety is optionally substituted in position 4 with C1-6alkyl, C1-6alkylcarbonyl or C1-6alkylsulfonyl.

[000345] In certain embodiments of formula I, R ¹ is a group of formula B, R ² is pyridin-2-yl substituted in position 5 with methyl or halo, R ³ is hydrogen, R ⁴ is methyl, R ⁶ is hydrogen , and R ⁵ is methoxymethyl; hydroxymethyl; morfolin-4-yl-methyl; pyrazin-2-yl; or 4-methanesulfonyl-piperazin-1-yl.

[000346] In certain modalities of formula I the compounds in question are more specifically formula II:

or a pharmaceutically acceptable salt thereof, where:

[000347] X is C or N;

[000348] R ¹¹ and R ¹² each independently is hydrogen; C1-6alkyl;

C1-6 alkyloxy; halo; halo-C1-6alkyl; halo-C1-6 alkoxy; hetero-C1-6alkyl; C1-6 alkylsulfonyl; or cyan; and [000349] R ¹ and R ⁵ are as defined here.

[000350] In certain embodiments of formula II, the compounds of the invention

llb;

where X, R ¹ , R ⁵ , R ¹¹ and R ¹² are as defined here.

[000351] In certain embodiments of formula I, the compounds in question are more specifically of formula ll:

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or a pharmaceutically acceptable salt thereof, wherein X, R ¹ , R ⁵ , R ¹¹ and R ¹² are as defined herein.

[000352] In certain modalities of any of formulas I, Ila, llb, or III, R ⁵ is:

on what:

[000353] ne 0, 1 or 2;

[000354] R ^c and R ^d each independently is hydrogen or C1-6 alkyl; [000355] R ^e is hydrogen, C1-6 alkyl, acetyl or C1-6 alkylsulfonyl; [000356] R ^f and R ^g each independently is hydrogen or C1-6 alkyl; [000357] R ^h and R 'each independently is hydrogen, C1-6alkyl, fluorine, hydroxy or C1-6alkyloxy;

[000358] R ^j and R ^k each independently is hydrogen or C1-6 alkyl; and [000359] R ^m , R ⁿ , R °, R ^p , R ^q and R ^r , each independently is hydrogen, C1-6alkyl, halo, C1-6alkoxy, C1-6alkylsulfonyl halo-C1-6alkyl, or cyan. [000360] In certain modalities of any of formulas I, Ila, llb, or III, R ⁵ is:

where R ^e is as defined here, or [000361] In certain embodiments of any of formulas I, Ila, llb, or III, R ⁵ is:

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where any of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^a , R ^b , R ^c , R ^d and R ^e is alkyl or contains an alkyl moiety, such alkyl is preferably lower alkyl, i.e., C 1 -C 6 alkyl, and more preferably C 1 -C 4 alkyl.

[000362] The invention also provides methods for treating a mediated or otherwise mediated disease or condition associated with the P2X3 receptor antagonist, P2X2 / 3 receptor antagonist, or both, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.

[000363] The disease can be genitourinary disease or urinary tract disease. In other circumstances, the disease may be a disease associated with pain. Urinary tract disease can be: reduced bladder capacity; frequent urination; urgent urinary incontinence; stress urinary incontinence; bladder hyper-reactivity; benign prostatic hypertrophy; prostatitis; detrusor hyper-reflexia; urinary frequency; nocturia; urinary urgency; overactive bladder; pelvic hypersensitivity; urethritis; prostatitis; pelvic pain syndrome; prostatodynia; cystitis; or idiopathic bladder hypersensitivity.

[000364] The disease associated with pain can be: inflammatory pain; surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve damage; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; posttraumatic injury; or pain associated with irritable bowel syndrome.

[000365] The disease can be a respiratory disorder, such as chronic obstructive pulmonary disorder (COPD), asthma, or bronchospasm, or a gastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD) , biliary colic and other biliary disorders, renal colic, diarrhea dominant IBS, pain associated with GI distension.

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44/98 [000366] Representative compounds according to the methods of the invention are shown in Table 1. TABLE 1

No. Name (Autonom®) M + H 1 4'-methyl-5- [1,2,3] triazole (2-methoxy-1-methyl-ethyl) -amide-i-1-steak n i-3-carboxylic acid 351 2 4'-Methyl-5- [1,2,4] triazole (2-methoxy-1-methyl-ethyl) -amide -1 i-steak n i l-3-carboxylic acid 351 3 4'-methyl-5- [1,2,3] triazol2-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide 351 4 2'-Fluoro-4'-methyl-5- [1,2,4] triazolo [4,3-a] pyridin-3-yl-biphenyl- (1-pyrazin-2-yl-ethyl) -amide 3-carboxylic 453 5 4'-methyl-5- (5-methyl [1,2,3] triazole-1-yl) -biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide 365 6 4'-Methyl-5- (5-methyl [1,2,3] triazol-1-yl) -biphenyl-3-carboxylic acid ((R) -2-methoxy-1-methyl-ethyl) -amide 365 7 4'-methyl-5- (5-methyl- [1,2,3] triazol-1-yl) -biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 399 8 5- (5-lsopropyl [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide 379 9 5- (5-lsopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide 393 10 5- (5-lsopropyl [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid ((R) -2-methoxy-1-methyl-ethyl) -amide 393 11 5- (5-lsopropyl [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 379 12 5- (5-lsopropyl- [1,2,3] triazol1 -yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 427 13 4'-Methyl-5- (5-methyl [1,2,3] triazol-1-yl) -biphenyl-3-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide 351 14 5- (5-lsopropyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide 393 15 5- (5-lsopropyl [1,2,4] triazole-1-yl) -4'-methyl-biphenyl-3-carboxylic acid ((R) -2-methoxy-1-methyl-ethyl) -amide 393 16 5- (5-lsopropyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 379 17 5- (5-lsopropyl [1,2,4] triazole-1-yl) -4'-methyl-biphenyl-3-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide 379

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No. Name (Autonom®) M + H 18 5- (5-lsopropyl- [1,2,4] triazol1 -yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 427 19 5- (3-lsopropyl- [1,2,4] triazol4-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 427 20 5- (3-lsopropyl [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid ((R) -2-methoxy-1-methyl-ethyl) -amide 393 21 5- (3-lsopropyl [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide 379 22 2'-Fluoro-5- (5isopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl- ((R) -2-methoxy-1-methyl-ethyl) -amide 3-carboxylic 411 23 2'-Fluoro-5- (5-isopropyl [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 397 24 2'-Fluoro-5- (5isopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl- ((S) -2-hydroxy-1-methyl-ethyl) -amide 3-carboxylic 397 25 2'-Fluoro-5- (5-isopropyl [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 445 26 5- (3-lsopropyl [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 379 27 5- (5-lsopropyl-3methyl- [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3 acid ((R) -2-methoxy-1-methyl-ethyl) -amide -carboxylic 407 28 5- (5-lsopropyl-3-methyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 393 29 5- (5-lsopropyl-3methyl- [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3 acid ((S) -2-hydroxy-1-methyl-ethyl) -amide -carboxylic 393 30 5- (5-lsopropyl-3-methyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 441 31 5- (3-lsopropyl-5-methyl [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 441 32 5- (3-lsopropyl-5methyl- [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3 acid ((R) -2-methoxy-1-methyl-ethyl) -amide -carboxylic 407 33 2'-Fluoro-5- (5isopropyl- [1,2,4] triazol-1-yl) -4'-methyl-biphenyl- ((R) -2-methoxy-1-methyl-ethyl) -amide 3-carboxylic 411 34 2'-Fluoro-5- (5-isopropyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 397 35 2'-Fluoro-5- (5isopropyl- [1,2,4] triazole-1-yl) -4'-methyl-biphenyl- ((S) -2-hydroxy-1-methyl-ethyl) -amide 3-carboxylic 397 36 2'-Fluoro-5- (5-isopropyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 445

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No. Name (Autonom®) M + H 37 5- (3-ethyl-3/7 [1,2,3] triazol-4-yl) -4'-methyl-biphenyl- ((R) -2-methoxy-1-methyl-ethyl) -amide 3-carboxylic 379 38 5- (3-ethyl-3 / 7- [1,2,3] triazole-4yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 413 39 5- (1-Ethyl-1 H [1,2,3] triazol-4-yl) -4'-methyl-biphenyl-3 acid ((R) -2-methoxy-1-methyl-ethyl) -amide -carboxylic 379 40 5- (1-Ethyl-1 H [1,2,3] triazol-4-yl) -4'-methyl-biphenyl-3 acid ((S) -2-hydroxy-1-methyl-ethyl) -amide -carboxylic 365 41 5- (1-ethyl-1 / 7- [1,2,3] triazole-4yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 413 42 5- (4-Ethyl-4/7 [1,2,4] triazol-3-yl) -4'-methyl-biphenyl- ((S) -2-hydroxy-1-methyl-ethyl) -amide 3-carboxylic 365 43 5- (4-ethyl-4 / 7- [1,2,4] triazole-3yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 413 44 4'-Chloro-5- (5-dimethylamino [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 448 45 5- (5-Methoxymethyl [1,2,4] triazole-1-yl) -4'-methyl-biphenyl-3-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide 381 46 5- (5-Methoxymethyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 429 47 5- [5- (1-Methoxy-ethyl) [1,2,4] triazole-1-yl] -4'-methyl- ((S) -2-hydroxy-1-methyl-ethyl) -amide biphenyl-3-carboxylic 395 48 5- [5- (1-Methoxy-ethyl) [1,2,4] triazole-1-yl] -4'-methyl-biphenyl-3- (1-pyrazin-2-yl-ethyl) -amide carboxylic 443 49 5- [5- (1-Hydroxy-ethyl) [1,2,4] triazole-1-yl] -4'-methyl-biphenyl-3- (1-pyrazin-2-yl-ethyl) -amide carboxylic 429 50 4'-Chloro-5- (5-methoxy [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 435 51 4'-Chloro-5- [1,2,4] triazole-1-ylbiphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 405 52 4'-Chloro-5- (5-isopropoxy [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 463 53 5- (2-lsopropyl-2H [1,2,4] triazol-3-yl) -4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 427 54 5- (2-lsopropyl-2H [1,2,4] triazol-3-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide 379 55 N- (2-Hydroxy-1-methyl-ethyl) -3- (5-isopropyl- [1,2,4] triazol-1-yl) -5- (5methyl-pyridin-2-yl) -benzamide 153.0- 154.5C

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No. Name (Autonom®) M + H 56 3- (5-lsopropyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 428 57 N- (2-Hydroxy-1-methyl-ethyl) -3- [5- (1-methoxy-ethyl) - [1,2,4] triazol-1-yl] 5- (5-methyl-pyridin-2 -il) -benzamide 396 58 3- [5- (1-Methoxy-ethyl) - [1,2,4] triazol-1-yl] -5- (5-methyl-pyridin-2-yl) -N (1-pyrazin-2-yl -ethyl) -benzamide 444 59 3- (5-Cyclopropyl- [1,2,4] triazol-1-yl) -N- (2-hydroxy-1-methyl-ethyl) -5 (5-methyl-pyridin-2-yl) -benzamide 378 60 3- (5-Cyclopropyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 426 61 5- [5- (1-Dimethylamino-ethyl) [1,2,4] triazol-1-yl] -4'-methyl-biphenyl-3- (1-pyrazin-2-yl-ethyl) -amide carboxylic 456 62 5- [5- (1 Dimethylamino-ethyl) - [1,2,4] triazole-1-yl] -4'-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 456 63 4'-methyl-5- (5propyl- [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid (2-dimethylamino-1-methyl-ethyl) -amide 406 64 4'-methyl-5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid cyclopropylamide 387 65 4'-Methyl-5- (5trifluoromethyl- [1,2,4] triazole-1-yl) -biphenyl-3-carboxylic acid ((S) -2-hydroxy-1-methyl-ethyl) -amide 405 66 4'-methyl-5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide 453 67 4'-Methyl-5- (5trifluoromethyl- [1,2,4] triazol-1-yl) -biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 453 68 N-Cyclopropyl-3- (5-methyl-pyridin-2-yl) -5- (5-methyl- [1,2,4] triazol-1 yl) -benzamide 334 69 3- [5- (1,1-Difluoro-ethyl) - [1,2,4] triazol-1-yl] -N- (5-methyl-pyrazin-2ylmethyl) -5- (5-methyl-pyridin- 2-yl) -benzamide 70,071.0Ό 70 3- [5- (1,1-Difluoro-ethyl) - [1,2,4] triazol-1-yl] -5- (5-methyl-pyridin-2-yl) N- (1-pyrazin-2 -yl-ethyl) -benzamide 70,071.0Ό 71 3- [5- (1,1-Difluoro-ethyl) - [1,2,4] triazol-1-yl] -N - ((S) -2-hydroxy-1methyl-ethyl) -5- (5- methyl-pyridin-2-yl) -benzamide 76,077.0Ό 72 N-Cyclopropyl-3- [5- (1,1-difluoro-ethyl) - [1,2,4] triazol-1-yl] -5- (5methyl-pyridin-2-yl) -benzamide 200, ΟΣΟΙ, 0Ό 73 3- (5-Chloro-pyridin-2-yl) -5- [5- (1,1-difluoro-ethyl) - [1,2,4] triazol-1-yl] N - ((S) -2 -hydroxy-1-methyl-ethyl) -benzamide 159.0160, OO 74 3- (5-Chloro-pyridin-2-yl) -5- (5-isobutyl- [1,2,4] triazol-1-yl) -N- (1 - 462

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No. Name (Autonom®) M + H pyrazin-2-yl-ethyl) -benzamide 75 3- (5-Cyclobutyl- [1,2,4] triazol-1-yl) -N-cyclopropyl-5- (5-methylpyridin-2-yl) -benzamide 374 76 3- (5-Chloro-pyridin-2-yl) -5- (5-difluoromethyl- [1,2,4] triazol-1-yl) -N (1-pyrazin-2-yl-ethyl) -benzamide 456 77 3- (5-Chloro-pyridin-2-yl) -5- (5-difluoromethyl- [1,2,4] triazol-1-yl) -N (5-methyl-pyrazin-2-ylmethyl) -benzamide 456 78 3- (5-Chloro-pyridin-2-yl) -5- (5-difluoromethyl- [1,2,4] triazol-1-yl) -N ((S) -2-hydroxy-1-methyl-ethyl ) -benzamide 408 79 3- (5-Chloro-pyridin-2-yl) -N- (1-pyrazin-2-yl-ethyl) -5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -benzamide 474 80 3- (5-Chloro-pyridin-2-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 474 81 3- (5-Chloro-pyridin-2-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 426 82 3- (5-tert-Butyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5 (5-methyl-pyridin-2-yl) - benzamide 422 83 3- (5-tert-Butyl- [1,2,4] triazol-1-yl) -5- (5-chloro-pyridin-2-yl) -N- (1 pyrazin-2-yl-ethyl) - benzamide 462 84 3- (5-tert-Butyl- [1,2,4] triazol-1-yl) -5- (5-chloro-pyridin-2-yl) -N- (5methyl-pyrazin-2-ylmethyl) -benzamide 462 85 3- (5-tert-Butyl- [1,2,4] triazol-1-yl) -5- (5-chloro-pyridin-2-yl) -N - ((S) 2-hydroxy-1-methyl -ethyl) -benzamide 414 86 3- (5-Cyclobutyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5 (5-methyl-pyridin-2-yl) -benzamide 85,086.0Ό 87 3- (5-Cyclobutyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 440 88 3- (5-Cyclobutyl- [1,2,4] triazol-1-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) 5- (5-methyl-pyridin-2-yl ) -benzamide 95,096, OO 89 3- (5-Chloro-pyridin-2-yl) -5- (5-isobutyl- [1,2,4] triazol-1-yl) -N- (5methyl-pyrazin-2-ylmethyl) -benzamide 462 90 3- (5-Chloro-pyridin-2-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) -5- (5- isobutyl- [1,2,4] triazol-1-yl) -benzamide 414 91 3- (5-Chloro-pyridin-2-yl) -5- (5-fluoromethyl- [1,2,4] triazol-1-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 438 92 3- (5-Chloro-pyridin-2-yl) -5- (5-fluoromethyl- [1,2,4] triazol-1-yl) -N- (5methyl-pyrazin-2-ylmethyl) -benzamide 438

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No. Name (Autonom®) M + H 93 3- (5-Chloro-pyridin-2-yl) -5- (5-fluoromethyl- [1,2,4] triazol-1-yl) -N ((S) -2-hydroxy-1-methyl-ethyl ) -benzamide 390 94 3- (5-tert-Butyl- [1,2,4] triazol-1-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) 5- (5-methyl-pyridin-2 -il) -benzamide 394 95 3- (5-tert-Butyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -N- (1 pyrazin-2-yl-ethyl) - benzamide 442 96 N-Cyclopropyl-3- (5-methyl-pyridin-2-yl) -5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -benzamide 388 97 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- (5-methyl-pyridin-2-yl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 406 98 3- (5-methyl-pyridin-2-yl) -N- (1-pyrazin-2-yl-ethyl) -5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -benzamide 454 99 N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 169, ΟΙ 70.0C 100 3- (5-methyl-pyridin-2-yl) -5- (5-methyl- [1,2,4] triazol-1-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 400 101 N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-methyl [1,2,4] triazol-1-yl) -benzamide 400 102 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-methyl [1,2,4] triazol-1-yl ) -benzamide 352 103 5- [5- (1Dimethylamino-ethyl) - [1,2,4] triazole-1-yl] -4'-methyl-biphenyl-3-carboxylic acid (2-dimethylamino-1-methyl-ethyl) -amide 435 104 5- [5- (1-Dimethylamino-ethyl) [1,2,4] triazole-1-yl] -4'-methyl-biphenyl-3-carboxylic acid cyclopropylamide 390 105 5- [5- (1-Dimethylamino-ethyl) - [1,2,4] triazole-1-yl] -4'-methyl-biphenyl acid ((S) -2-hydroxy-1-methyl-ethyl) -amide -3carboxylic 408 106 3- (5-Chloro-pyridin-2-yl) -5- (5-ethyl- [1,2,4] triazol-1-yl) -N- (1-pyrazin2-yl-ethyl) -benzamide 86,087.0C 107 3- (5-Chloro-pyridin-2-yl) -5- (5-ethyl- [1,2,4] triazol-1-yl) -N - ((S) -2hydroxy-1-methyl-ethyl) -benzamide 94,095.0C 108 3- (5-Chloro-pyridin-2-yl) -N-cyclopropyl-5- (5-ethyl- [1,2,4] triazol-1-yl) benzamide 190.0191, OC 109 3- (5-Chloro-pyridin-2-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5- (5-propyl [1,2,4] triazol-1-yl) -benzamide 127.0128, OC 110 3- (5-Chloro-pyridin-2-yl) -5- (5-propyl- [1,2,4] triazol-1-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 87,088, OC

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No. Name (Autonom®) M + H 111 3- (5-Chloro-pyridin-2-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) -5- (5-propyl [1,2,4] triazol-1-yl ) -benzamide 146.0147.0Ό 112 3- (5-Chloro-pyridin-2-yl) -N-cyclopropyl-5- (5-propyl- [1,2,4] triazol-1 yl) -benzamide 148,0149.0Ό 113 N-Cyclopropyl-3- (5-methyl-pyridin-2-yl) -5- (5-propyl- [1,2,4] triazol-1 yl) -benzamide 362 114 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-propyl [1,2,4] triazol-1-yl ) -benzamide 380 115 3- (5-methyl-pyridin-2-yl) -5- (5-propyl- [1,2,4] triazol-1-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 428 116 N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-propyl [1,2,4] triazol-1-yl) -benzamide 428 117 5- (1-lsopropyl-1 H [1,2,4] triazol-3-yl) -4'-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 427 118 3- (5-lsobutyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 442 119 3- (5-lsobutyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5 (5-methyl-pyridin-2-yl) -benzamide 442 120 3- (5-Chloro-pyridin-2-yl) -5- (5-isopropyl- [1,2,4] triazol-1-yl) -N- (1 pyrazin-2-yl-ethyl) -benzamide 448 121 3- (5-Chloro-pyridin-2-yl) -5- (5-isopropyl- [1,2,4] triazol-1-yl) -N- (5methyl-pyrazin-2-ylmethyl) -benzamide 448 122 3- (5-Chloro-pyridin-2-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) -5- (5- isopropyl- [1,2,4] triazol-1-yl) -benzamide 400 123 3- (5-Chloro-pyridin-2-yl) -N-cyclopropyl-5- (5-isopropyl [1,2,4] triazol-1-yl) -benzamide 382 124 3- (5-Chloro-pyridin-2-yl) -5- (5-ethyl- [1,2,4] triazol-1-yl) -N- (5-methylpyrazin-2-ylmethyl) -benzamide 72,073, OO 125 3- (5-Cyclopropyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2-ylmethyl) 5- (5-methyl-pyridin-2-yl) -benzamide 426 126 N-Cyclopropyl-3- (5-ethyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) benzamide 348 127 3- (5-ethyl- [1,2,4] triazol-1-yl) -N - ((S) -2-hydroxy-1-methyl-ethyl) -5- (5methyl-pyridin-2-yl) -benzamide 366 128 3- (5-ethyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -N- (1-pyrazin2-yl-ethyl) -benzamide 414 129 3- (5-ethyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5- (5methyl-pyridin-2-yl) -benzamide 414

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No. Name (Autonom®) M + H 130 N-Cyclopropyl-3- (5-isobutyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin2-yl) -benzamide 376 131 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- (5-isobutyl- [1,2,4] triazol-1-yl) -5 (5-methyl-pyridin-2-yl ) -benzamide 394 132 3- (5-lsopropyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2-ylmethyl) -5 (5-methyl-pyridin-2-yl) -benzamide 428 133 3- [5- (1-Methoxy-ethyl) - [1,2,4] triazol-1-yl] -N- (5-methyl-pyrazin-2ylmethyl) -5- (5-methyl-pyridin-2- il) -benzamide 444 134 5- [5- (1-Methoxy-ethyl) [1,2,4] triazole-1-yl] -4'-methyl-biphenyl-3- (5-methyl-pyrazin-2-ylmethyl) -amide carboxylic 444 135 2'-Fluoro-5- (5isopropyl- [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 445 136 5- (5-lsopropyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 427 137 5- (2-lsopropyl-2H [1,2,4] triazol-3-yl) -4'-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 427 138 5- (3-lsopropyl-5methoxy- [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl) -amide 457 139 N-Cyclopropyl-3- [5- (1-dimethylamino-ethyl) - [1,2,4] triazol-1-yl] -5- (5methyl-pyridin-2-yl) -benzamide 391 140 3- [5- (1-Dimethylamino-ethyl) - [1,2,4] triazol-1-yl] -N - ((S) -2-hydroxy-1 methyl-ethyl) -5- (5-methyl -pyridin-2-yl) -benzamide 409 141 3- [5- (1-Dimethylamino-ethyl) - [1,2,4] triazol-1-yl] -N- (5-methyl-pyrazin2-ylmethyl) -5- (5-methyl-pyridin-2- il) -benzamide 457 142 3- [5- (1-Dimethylamino-ethyl) - [1,2,4] triazol-1-yl] -5- (5-methyl-pyridin2-yl) -N- (1-pyrazin-2-yl- ethyl) -benzamide 457 143 N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-phenyl [1,2,4] triazol-1-yl) -benzamide 462 144 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-phenyl [1,2,4] triazol-1-yl ) -benzamide 414 145 3- [5- (2,2-Difluoro-ethyl) - [1,2,4] triazol-1-yl] -N- (5-methyl-pyrazin-2ylmethyl) -5- (5-methyl-pyridin- 2-yl) -benzamide 414 146 3- [5- (2,2-Difluoro-ethyl) - [1,2,4] triazol-1-yl] -N - ((S) -2-hydroxy-1methyl-ethyl) -5- (5- methyl-pyridin-2-yl) -benzamide 366 147 3- [5- (2-Methoxy-ethyl) - [1,2,4] triazol-1-yl] -N- (5-methyl-pyrazin-2ylmethyl) -5- (5-methyl-pyridin-2- il) -benzamide 444 148 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- [5- (2-methoxy-ethyl) - [1,2,4] triazol1 -yl] -5- (5-methyl- pyridin-2-yl) -benzamide 396

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No. Name (Autonom®) M + H 149 3- [5- (2-Ethoxy-ethyl) - [1,2,4] triazol-1-yl] -N- (5-methyl-pyrazin-2ylmethyl) -5- (5-methyl-pyridin-2- il) -benzamide 458 150 3- [5- (2-Ethoxy-ethyl) - [1,2,4] triazol-1-yl] -N - ((S) -2-hydroxy-1-methyl- ethyl) -5- (5-methyl-pyridin-2-yl) -benzamide 410 151 3- (5-Azetidin-3-yl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2ylmethyl) -5- (5-methyl-pyridin-2-yl) -benzamide 441 152 3- (5-Cyclobutyl- [1,2,4] triazol-1-yl) -N- (6-methyl-pyridazin-3-ylmethyl) 5- (5-methyl-pyridin-2-yl) -benzamide 440 153 3- (5-lsopropyl- [1,2,4] triazol-1-yl) -N- (1-methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl) -5- (5- methyl-pyridin-2-yl) -benzamide 443 154 3- [5- (2-Methoxy-ethyl) -3-methyl- [1,2,4] triazol-1-yl] -N- (5-methylpyrazin-2-ylmethyl) -5- (5-methyl- pyridin-2-yl) -benzamide 458 155 N - ((S) -2-Hydroxy-1-methyl-ethyl) -3- [5- (2-methoxy-ethyl) -3-methyl [1,2,4] triazol-1-yl] -5- (5-methyl-pyridin-2-yl) -benzamide 410 156 3- [5- (2-Hydroxy-2-methyl-propyl) - [1,2,4] triazol-1-yl] -N- (5-methylpyrazin-2-ylmethyl) -5- (5-methyl- pyridin-2-yl) -benzamide 458 157 3- [5- (1 - methyl-azeti di n-3-i I) - [1,2,4] tri-azo I-1 - i I] -N- (5-methyl Ip i razi n2-ylmethyl ) -5- (5-methyl-pyridin-2-yl) -benzamide 455 158 3- (5-Chloro-pyridin-2-yl) -5- [5- (1-dimethylamino-ethyl) - [1,2,4] triazol1-yl] -N- (5-methyl-pyrazin-2- ilmethyl) -benzamide 87,088.0Ό 159 3- (5-lsopropyl- [1,2,4] triazol-1-yl) -N- (1-methyl-2-oxo-1,2-dihydropyridin-4-ylmethyl) -5- (5- methyl-pyridin-2-yl) -benzamide 443 160 N- (1-methyl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl) -3- (5-methylpyridin-2-yl) -5- (5-trifluoromethyl- [1,2, 4] triazole-1-yl) -benzamide 469 161 N- (6-methyl-pyridazin-3-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 195.4- 196.0Ό 162 N- (1-ethyl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl) -3- (5-isopropyl [1,2,4] triazol-1-yl) -5- (5 -methyl-pyridin-2-yl) -benzamide 457 163 N- (1-ethyl-2-oxo-1,2-dihydro-pyridin-4-ylmethyl) -3- (5-methyl-pyridin2-yl) -5- (5-trifluoromethyl- [1,2, 4] triazole-1-yl) -benzamide 483 164 4-Fluoro-N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 472 165 4-Fluoro-N - ((S) -2-hydroxy-1-methyl-ethyl) -3- (5-methyl-pyridin-2-yl) -5 (5-trifluoromethyl- [1,2,4] triazole -1-yl) -benzamide 424 166 3- (5-methyl-pyridin-2-yl) -N- (2-methyl-pyrimidin-5-ylmethyl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 454 167 2-Fluoro-N - ((S) -2-hydroxy-1-methyl-ethyl) -3- (5-methyl-pyridin-2-yl) -5 (5-trifluoromethyl- [1,2,4] triazole -1-yl) -benzamide 424

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No. Name (Autonom®) M + H 168 2-Fluoro-3- (5-methyl-pyridin-2-yl) -N- (1-pyrazin-2-yl-ethyl 1) -5- (5trifluoromethyl- [1,2,4] triazol-1-yl ) -benzamide 472 169 2-Fluoro-N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 472 170 4-Fluoro-3- (5-methyl-pyridin-2-yl) -N- (1-pyrazin-2-yl-ethyl 1) -5- (5trifluoromethyl- [1,2,4] triazol-1-yl ) -benzamide 472 171 3- (5-methyl-pyridin-2-yl) -N- (5-methyl-pyrimidin-2-ylmethyl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 454 172 2-Fluoro-5- (5-isopropyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2- ilmethyl) -3- (5-methyl-pyridin-2-yl) -benzamide 446 173 2-Fluoro-5- (5-isopropyl- [1,2,4] triazol-1-yl) -3- (5-methyl-pyridin-2yl) -N- (1-pyrazin-2-yl-ethyl) -benzamide 446 174 2-Fluoro-N - ((S) -2-hydroxy-1-methyl-ethyl) -5- (5-isopropyl [1,2,4] triazol-1-yl) -3- (5-methyl-pyridin -2-yl) -benzamide 398 175 4-Fluoro-3- (5-isopropyl- [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin-2- ilmethyl) -5- (5-methyl-pyridin-2-yl) -benzamide 446 176 2-Fluoro-N- (6-methyl-pyridazin-3-ylmethyl) -3- (5-methyl-pyridin-2-yl) - 5- (5-trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 472 177 2-Fluoro-3- (5-methyl-pyridin-2-yl) -N- (5-methyl-pyrimidin-2-ylmethyl) - 5- (5-trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 472 178 2-Fluoro-3- (5-methyl-pyridin-2-yl) -N- (2-methyl-pyrimidin-5-ylmethyl) - 5- (5-trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 472 179 N - ((R) -1-methyl-2-morpholin-4-yl-ethyl) -3- (5-methyl-pyridin-2-yl) -5- (5- trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 475 180 3- (5-methyl-pyridin-2-yl) -N - ((S) -1-pyrazin-2-yl-ethyl) -5- (5trifluoromethyl- [1,2,4] triazol-1-yl) -benzamide 454

[000367] Compounds of the present invention can be made by a variety of methods described in the illustrative synthetic reaction schemes shown and described below.

[000368] The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following the procedures set out in the standard references. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these repeating schemes 870180137880, of 10/04/2018, p. 66/114

54/98 synthetic action can be made and will be suggested to someone skilled in the art having referred to the description contained in this Order.

[000369] The starting materials and intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[000370] Unless otherwise specified, the reactions described here are preferably conducted under an atmosphere inert to atmospheric pressure in a reaction temperature range of about -78Ό to about 150Ό, more preferably from about 0 ° C to about 125Ό, and most preferably is convenient at about local (or ambient) temperature (RT), for example, about 20Ό.

[000371] Scheme A below illustrates a synthetic procedure usable for preparing the specific compounds of formula I, where Y is an optional starting group, two of Zi, Z2 and Z3 are optionally nitrogen and the other is carbon, and X, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ^c and R ^d are as defined here. SCHEME

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55/98 [000372] In step 1 of Scheme A, nitrobenzoic acid a is subjected to iodination under sulfuric acid conditions to provide iodo-nitrobenzoic acid b. The benzoic acid compound b is reacted with the arylboronic acid compound c in the presence of tetrakis- (triphenylphosphino) palladium catalyst to provide the biphenyl acid compound d. The acid group of biphenyl acid d is protected by esterification in step 3 to form biphenyl acid methyl ester e. Biphenyl ester and is then subjected to reduction to form biphenylamine f in step 4. An iodination reaction is carried out in step 5 by treating biphenylamine f with methylene iodide or as an iodination reagent to provide the iodine compound g. In step 6 the ester compound group g is hydrolyzed to give the acid compound h. In step 7 an amide formation is achieved by reacting the biphenyl iodine compound h with amine i in the presence of carbodiimide, to provide compound j. Compound j is then reacted with heteroaryl reagent k, to yield compound m which is a compound of formula I according to the invention. Heteroaryl reagent k may comprise a pyrrole, imidazole, pyrazole or triazole. In certain modalities it can be halo, and in other modalities it can be -B (OH) 2. In still other modalities, Y may be absent. [000373] Many variations of Scheme A are possible and will suggest to those skilled in the art. For example, the methyl ester formed in step 3 can be replaced by other lower alkyl esters using the appropriate alcohol in step 3. In many embodiments, step 8 can be performed before steps 6 and 7, so that the compound of iodobiphenyl g is reacted with reagent k. The resulting heteroaryl-substituted compound (not shown) then undergoes hydrolysis of the ester as in step 6, followed by amide formation as in step 7, to provide compound m. In still other embodiments, the formation of the amide from step 7 can be carried out at a more premature point in the sequence of events in Scheme A.

[000374] In certain embodiments, the compounds in question can be prepared by the procedure in Scheme B, where X, R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ ,

R ¹² and R ^d are as defined here.

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SCHEMEΒ

[000375] In step 1 of Scheme Β, the amine compound f (from Scheme A above) is treated with sodium nitrite in the presence of acid, followed by stannous chloride, to provide the hydrazine compound n. In step 2, a mixture of the amide compound and dimethyl acetamide dimethyl acetal is reacted with the hydrazine compound n to yield the p triazolyl compound.

In step 2, the acetal amide compound forms an imine of the formula s

R ^d ^^ N ^ N (CH ₃ ) ₂ θ that can be generated in situ in many modalities, without being isolated. The hydrolysis of the ester from step 3 and the formation of the amide from step 4 are carried out as described above for steps 6 and 7 of Scheme A.

[000376] As in the case of Scheme A, many variations in the procedure of Scheme B are possible within the scope of the invention. Specific details are described for producing the compounds of the invention in the Examples section below.

[000377] The compounds of the invention are usable for the treatment of a wide range of diseases, conditions and genitourinary disorders, including urinary tract disease associated with bladder outlet obstruction and urinary incontinence conditions such as reduced bladder capacity, frequency of urination, urge urinary incontinence, stress urinary incontinence, bladder hyper-reactivity, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyper-reflexia, frequency

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57/98 urinary, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urethritis, prostatitis, pelvic pain syndrome, prostatodynia, cystitis, and idiopathic bladder hypersensitivity, and similar symptoms related to overactive bladder.

[000378] The compounds of the invention are expected to find use as analgesics in the treatment of diseases and conditions associated with pain of a wide variety, including, but not limited to, inflammatory pain such as pain associated with arthritis (including rheumatoid arthritis and osteoarthritis), surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve damage, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, infection viral, parasitic or bacterial, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorders associated with such as irritable bowel syndrome. [000379] Also, the compounds of the invention are useful for treating respiratory disorders, including chronic obstructive pulmonary disorder (COPD), asthma, bronchospasm, and the like.

[000380] Additionally, the compounds of the invention are useful for treating gastrointestinal disorders, including Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, dominant IBS of diarrhea, associated pain distension Gl, and the like.

[000381] The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and / or prophylactic ingredients.

[000382] In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents serving similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably

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58/98

1-100 mg daily, and most preferably 1-30 mg daily, depending on numerous factors such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration , the indication to which the administration is directed, and the preferences and experience of the physician involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in the confidence of personal knowledge and disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.

[000383] The compounds of the invention can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral using a convenient daily dosing regimen that can be adjusted according to the degree of distress.

[000384] A compound or compounds of the invention, together with one or more adjuvants, vehicles, or conventional diluents, can be placed in the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms can be comprised of conventional ingredients in conventional proportions, with or without active compounds or additional principles, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurable with the dosage range. daily rate intended to be employed. The pharmaceutical compositions can be used as solids, such as filled tablets or capsules, semi-solids, powders, continuous-release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred

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59/98 (100) milligrams per tablet are therefore suitable representative unit dosage forms.

[000385] The compounds of the invention can be formulated in a wide variety of dosage forms for oral administration. The pharmaceutical compositions and dosage forms can comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. Pharmaceutically acceptable vehicles can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid vehicle can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the vehicle in general is a finely divided solid that is a mixture with the finely divided active component. In tablets, the active component in general is mixed with the vehicle that has the necessary binding capacity in the appropriate proportions and compacted in the desired shape and size. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and similar. The term preparation is intended to include the formulation of the active compound with encapsulating material as a vehicle, providing a capsule in which the active component, with or without vehicles, is surrounded by a vehicle that is in association with it. Similarly, cachets and lozenges are included. Pills, powders, capsules, pills, cachets, and lozenges can be solid forms suitable for oral administration.

[000386] Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are

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60/98 intended to be converted shortly before use into liquid preparations. Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or they can contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable dyes, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, dyes, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[000387] The compounds of the invention can be formulated for parenteral administration (for example, by injection, for example, bolus injection or continuous infusion) and can be presented as unit dose in ampoules, pre-filled syringes, infusion small volume or in multi-dose containers with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, aqueous polyethylene glycol solutions. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (for example, olive oil), and injectable organic esters (for example, ethyl oleate), and may contain formulating agents such as preserving, wetting, emulsifying or suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the constitution solution before use with a suitable vehicle, for example, sterile, pyrogen-free water.

[000388] The compounds of the invention can be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a

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61/98 transdermal patch. Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions can be formulated with an aqueous or oily base and in general will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active agents in a flavored base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwash liquids comprising the active ingredient in a suitable liquid carrier.

[000389] The compounds of the invention can be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is melted first and the active component is homogeneously dispersed, for example, by stirring. The homogeneous molten mixture is then poured into convenient sized molds, allowed to cool, and solidify.

[000390] The compounds of the invention can be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such vehicles as are known in the art to be appropriate.

[000391] The compounds in question can be formulated for nasal administration. Solutions or suspensions are directly applied to the nasal cavity using conventional means, for example, with a dropper, pipette or spray. The formulations can be supplied in a single or multidose form. In the last case of a dropper or pipette, this can be achieved by the patient by administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this can be achieved, for example, by means of a metered atomizing spray pump.

[000392] The compounds of the invention can be formulated for administration 870180137880, from 10/04/2018, p. 74/114

62/98 aerosol traction, particularly for the respiratory tract and including intranasal administration. The compound will generally have a small particle size, for example, on the order of five (5) microns or less. Such a particle size can be obtained by means known in the art, for example, by micronization. The active ingredient is provided in a pressurized package with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol can also conveniently contain a surfactant such as lecithin. The dose of drug can be controlled by a metering valve. Alternatively, the active ingredients can be provided in a dry powder form, for example, a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder vehicle will form a gel in the nasal cavity. The powder composition can be presented in unit dose form, for example, in capsules or cartridges of, for example, gelatin or blister packs from which the powder can be administered by means of an inhaler.

[000393] When desired, formulations can be prepared with enteric coatings adapted for administration of continuous or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when continuous release of the compound is required and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are often attached to a solid adhesive support to the skin. The compound of interest can also be combined with a penetration enhancer, for example, Azone (1dodecylazacycloheptan-2-one). Continuous release systems are inserted subcutaneously into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a lipid-soluble membrane, for example, silicone rubber, or a biodegradable polymer,

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63/98 for example, polylactic acid.

[000394] Pharmaceutical preparations are preferably in unit dosage forms. In such a way, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation, the package containing different amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[000395] Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by EW Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing a compound of the present invention are described below.

EXAMPLES [000396] The following preparations and examples are given to allow those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative of them.

[000397] Unless otherwise stated, all temperatures including melting points (ie, MP) are in degrees celsius (Ό). It should be appreciated that the reaction that produces the indicated and / or desired product may not necessarily result directly from the combination of two reagents that were added initially, that is, there may be one or more intermediates that are produced in the mixture that ultimately leads to formation of the indicated and / or desired product. The following abbreviations can be used in Preparations and Examples.

[000398] Abbreviations: DBU: 1,8-diazabiciclo [5.4.0] undec-7-eno; DCM: dichloromethane / methylene; chloride; DMF: Ν, Ν-dimethylformamide; DMAP: 4-dimethylaminopyridine; EDCI: 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide; EtOAc:

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64/98 ethyl acetate; EtOH: ethanol; gc: gas chromatography; HMPA: hexamethylphosphoramide; HOBt: N-Hydroxybenzotriazole; hplc: high performance liquid chromatography; mCPBA: m-chloroperbenzoic acid; MeCN: acetonitrile; NMM: N-methyl-morpholine; NMP: N-methyl pyrrolidinone; TEA: triethylamine; THF: tetrahydrofuran; LDA: lithium diisopropylamine; TLC: thin layer chromatography.

PREPARATION 1: (S) -2-METOXY-1-METHYL-ETHYLAMINE [000399] The synthetic procedure used in this preparation is outlined below in Scheme C.

ESQUEMAC

Step 1 H ₃ C _X Step 2 H, C ^ Step 3 H, C. D-Alaninn T oh -► O 1. LAH 2. (Boc) ₂ O NHBoc Ag ₂ O, Honey - I NHBoc CH ₃ HCI NH ₂ qu MeOH ²

STEP 1 (S) -BOC-2-AMINO-PROPANOL [000400] D-alanine (3.5 g, 39.3 mmols) was added in small portions to a suspension of L1AIH4 (2.89 g, 76.26 mmols ) in reflux THF. Reflux continued for 12 hours, then the reaction mixture was cooled to 0Ό, and the excess reagent was quenched by the careful addition of a 15% aqueous solution of NaOH (3 ml) and water (9 ml). After stirring at RT for 10 minutes, a solution of (Boc) ₂ O (8.31 g, 38.13 mmol) in CH ₂ Cl ₂ (40 ml) was added. The reaction mixture was stirred at 60Ό for 6 hours, cooled to RT, filtered through an anhydrous Na ₂ SO4 block, and the filtrate concentrated in vacuo. Purification of the residue by column chromatography on silica gel yielded (S) -Boc-2-amino-propanol as a white solid, yield: 63%. MS (M + H) = 176.

STEP 2 (S) -BOC-2-METHYXY-1-METHYL-ETHYLAMINE [000401] To a solution of (S) -Boc-2-amino-propanol (2.00 g, 11.4 mmol) was successively added Ag ₂ O (5.89 g, 25.4 mmols) and methyl sludge (16.00 g, 112.7 mmols) in RT. The reaction mixture was stirred at RT for 2 days. Solid was filtered and the filtrate was concentrated in vacuo to yield (S) -Boc-2-methoxy-1-methyl-ethylamine as a colorless oil which was used without further purification.

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STEP 3 (S) -2-METHOXY-1-METHYL-ETHYLAMINE [000402] (S) -Boc-2-methoxy-1-methyl-ethylamine was dissolved in MeOH (40 ml) and 3 M HCI (10 ml) have been added. The reaction mixture was stirred overnight in RT, then the solvent was removed under reduced pressure and the residue was coevaporated with additional EtOH (20 ml) to yield (S) -2methoxy-1-methyl-ethylamine as light brown oil in hydrochloride form (1.42 g, 100%). MS (M + H) = 90.

[000403] Similarly prepared was (S) -2-ethoxy-1-methyl-ethylamine.

[000404] Similarly prepared from L-alanine were (R) -2-methoxy-1-methyl-ethylamine and (R) -2-ethoxy-1-methyl-ethylamine.

PREPARATION 2: (S) -1-METHYL-2-MORFOLIN-4-IL-ETHYLAMINE [000405] The synthetic procedure used in this preparation is outlined below in Scheme D.

SCHEME D h ₃ c

OH

Step 1

Step 2

NHBoc MsCI, Et ₃ N NHBoc morpholine

K ₂ CO ₃

Step 3

STEP 1 METANOSULPHONIC ACID 2-TERC-BUTOXICARBONYLAMINE-PROPYL ESTER [000406] To a solution of (S) -Boc-2-amino-propanol (4.91 g, 0.028 mol), Et ₃ N (1.5 equiv .) in CH2 Cl2 at 0Ό methanesulfonyl chloride (1.1-1.2 equiv) was added. The reaction was stirred at 0Ό for 30 minutes. Water (5 ml) was added and the organic layer was separated, washed with saturated aqueous NaHCO ₃ , brine, and dried with MgSO4. The solvent was removed in vacuo to provide methanesulfonic acid 2-tert-butoxycarbonylamino-propyl ester as a white solid, yield: 98%. MS (M + H) = 254. STEP 2 ACID TERC-BUTYL ESTER (1-METHYL-2-MORFOLIN-4YL-ETHYL) -CARBAMIC

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66/98 [000407] To a solution of 2-tert-butoxycarbonylamino-propyl ester of methanesulfonic acid (23 mmols) in CH3CN (20 ml) was added morpholine (28 mmols) and K2CO3 (23 mmols) in TA. The reaction mixture was brought to 50Ό and kept at the same temperature overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure, and the residue was treated with CH2 Cl2 (50 ml) and H2O (50 ml). The organic layer was separated and the aqueous layer was extracted with CH2 Cl2. The combined organic layer was dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate) to yield tert-butyl ester (1-methyl-2-morpholin-4-ylethyl) -carbamic acid as a viscous liquid, yield: 62%. MS (M + H) = 245. STEP 3 (S) -1-METHYL-2-MORFOLIN-4-IL-ETHYLAMINE [000408] To a solution of acid tert-butyl ester (1-methyl-2-morpholin -4-yl-ethyl) -carbamic (0.30 g, 1.22 mmol) in methanol (10 ml) 2N HCl (5 ml) was added at 0Ό. The reaction mixture was allowed to warm to RT and stirred overnight. The solvent was removed in vacuo to give (S) -1-methyl-2-morpholin-4-yl-ethylamine as a light yellow solid (250 mg, 96%). MS (M + H) = 145.

[000409] Similarly prepared were (S) -1-methyl-2-thiomorpholin-4-yl-ethylamine, (S) -1 - [4- (2-amino-propyl) -piperazin-1-yl] -ethanone, (S) -1 - (2-amino-propyl) -piperidin-4-ol, (S) -1 - (2-amino-propyl) -piperidin-3-ol, (S) -1-methyl-2- (4-methyl-piperazin-1-yl) -ethiamine, (S) -1-methyl-2- (4-methanesulfonyl-piperazin-1-i) -ethiamine, (S) -4- (2-amino-propyl ) -piperazin-2-one, 1-methyl-2-pi peridi n-1-yl-ethylamine, 1 - (2amino-propyl) -pyrol id in-3-ol, (S) -2- ( 4-Methoxy-piperidin-1-yl) -1-methyl-ethylamine, (S) -2- (3-Methoxy-piperidine n-1 -yl) -1-methyl-ethylamine, (S) -2- (4 -Methanesulfonyl-piperidin-1-yl) -1-methyl-ethylamine, and other 2-amino-1-heterocyclyl propanes. PREPARATION 3: (S) -2- (1,1-DIOXO-1LAMBDA * 6 * -TIOMORFOLIN-4-IL) -1METHY-ETHYLAMINE [000410] The synthetic procedure used in this preparation is outlined below in Scheme E.

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ΗΓ

Step 1 ο

EDCI /

HOBt

Step 2

TFA o

Step 3

Step 4

O

BH.

O

SCHEME

STEP 1 (1-METHYL-2-OXO-2-THIOMORFOLIN-4-IL-ETHYL) -CARBAMIC TERC-BUTYL ESTER [000411] To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmols), HOBt (22.2 mmols), NMP (22.2 mmols) and EDCI (22.2 mmols) in CH2CI2 was added thiomorpholine (2.29 g, 22.2 mmols) at 0Ό. The reaction mixture was stirred at 0Ό overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na ₂ SO4. The solvent was removed in vacuo to give (1-methyl-2-oxo-2thiomorpholin-4-yl-ethyl) -carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M + H) = 275. STEP 2 ACID TERC-BUTYL ESTER [2- (1,1-DIOXO-1 LAMBDA * 6 * -TIOMORFOLIN-4-IL) -1-METHYL-2-OXO-ETHY ] -CARBAMIC [000412] To a solution of tert-butyl ester of (1-methyl-2-oxo-2tiomorphin-4-yl-ethyl) -carbamic acid (5.0g, 18.2 mmols) in CH2CI2 m-CPBA (11.4 g, 46.25 mmols) at 0Ό. The reaction mixture was stirred at RT overnight. Solids were removed by filtration and the filtrate was washed with Na ₂ S ₂ O3 and dried over Na ₂ SO4. The solvent was removed in vacuo to give [2- (1,1-Dioxo-1lambda * 6 * -thiomorfolin-4yl) -1-methyl-2-oxo-ethyl] -carbamic acid tert-butyl ester (5, 6 g), 100% yield. MS (M + H) = 307. STEP 3 2-AMINO-1- (1,1-DIOXO-1 LAMBDA * 6 * -TIOMORFOLIN-4-IL) -PROPAN-1-ONA [000413] To an ester solution tert-butyl [2- (1,1-Dioxo1 lambda * 6 * -tiomorfolin-4-yl) -1-methyl-2-oxo-ethyl] -carbamic acid (5.6 g, 18.2 mmol) in CH2 Cl2 (70 ml) trifluoroacetic acid (5 ml) was added at 0Ό. The mixture 870180137880, of 10/04/2018, p. 80/114

The reaction was allowed to warm to RT and was stirred for 3 hours. After removal of CH2Cl2 and excess trifluoroacetic acid under reduced pressure, 2-amino-1- (1,1-dioxo-1lambda * 6 * -tiomorfolin-4-yl) -propan-1-one (6.0 g, yield 100%) was obtained as a white solid. MS (M + H) = 207.

STEP 4 (S) -2- (1,1-DIOXO-1 LAMBDA * 6 * -TIOMORFOLIN-4-IL) -1-METHYL-ETHYLAMINE [000414] A mixture of 2-amino-1- (1,1- dioxo-1 lambda * 6 * -tiomorfolin-4il) -propan-1-one (6.0 g, 18.2 mmols) and BH3 (1 M in THF, 110 ml) was heated to reflux for 48 h, then cooled to TA and extinguished by MeOH. The volatile was removed under vacuum. 2 N HCl (100 ml) was added to the residue and heated to reflux for 18 h. Solvent was removed in vacuo to give (S) -2- (1,1-Dioxo-1lambda * 6 * -thiomorpholin-4-yl) -1-methyl-ethylamine (4.5 g) as a white solid, yield 90% . MS (M + H) = 193.

PREPARATION 4: 1-PIRAZIN-2-IL-ETHYLAMINE [000415] The synthetic procedure used in this preparation is outlined below in Scheme F.

SCHEME

CH ₃ CO ₂ NH ₄ , NaBH ₃ CN

[000416] To a solution of 1-pyrazin-2-yl-ethanone (2.0 g, 15.85 mmols) and ammonium acetate (19.337 g, 158.5 mmols) in methanol (50 ml) was added cyanoborohydride sodium (0.7 g, 11.1 mmols) in one portion. The reaction mixture was stirred overnight at RT. After removal of methanol, water (20 ml) was added to the residue and the resulting solution was basified by adding sodium hydroxide to pH = 13. The aqueous solution was extracted with dichloromethane and the combined organic phase was dried over sodium sulfate. Removal of the solvent under reduced pressure gave 14.62 g of 1pyrazin-2-yl-ethylamine, yield: 75%. MS (M + H) = 124.

[000417] Similarly prepared from the appropriate heteroaryl methyl ketones or phenyl methyl ketones were: 1-pyridin-2-yl-ethylamine, 1-pyridin-3-yl-ethylamine,

-pi ridi η-4-i l-ethylamine, 1 - (2-fluoro-phenyl) -ethylamine, 1 - (3-fluoro-phenyl) -ethylamine,

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- (4-methanesulfonyl-phenyl) -ethylamine, 1-thien-3-yl-ethylamine, 1-furan-2-yl-ethylamine, 1- (5-methyl-furan) -2-yl-ethylamine , 1-thiazol-2-yl-ethylamine, 1-thien-2-yl-ethylamine, 1-pyridine η-2-i-1-ethylamine, C- (6-methyl-pyridazin-3-yl) -methylamine, C- (5-methylpyrazin-2-yl) -methylamine, and 1-pyridazin-4-yl-ethylamine.

PREPARATION 5: (2-METHYXY-1-METHYL-ETHYL) -ACID ACID 5-IODO-4'METHYL-BYPHENYL-3-CARBOXYX [000418] The synthetic procedure used in this preparation is outlined below in Scheme G.

ESQUEMAG

STEP 1 3-IODO-5-NITRO-BENZOIC ACID [000419] To a stirred solution of iodine (137.95 g, 0.5436 mmol) smoked sulfuric acid (250 ml) was added m-nitrobenzoic acid (64.6 g , 0.3866 mmol) in RT. The reaction mixture was slowly heated to 85Ό over 2 hours and stirred at the same temperature for another 12 hours. The reaction mixture was cooled to RT and poured into ice, and the aqueous solution was extracted with dichloromethane. The organic phase was separated and washed with water, 2.0 M Na2S2O3 solution and brine, and then dried over Na2SO4. The solvent was removed under reduced pressure to yield 3 iodo-5-nitrobenzoic acid as a light yellow solid 111 g, 98% yield. MS (M + H) = 294.

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STEP 2 4'-METHYL-5-NITRO-BYPHENYL-3-CARBOXYLIC ACID [000420] To a stirred solution of 3-iodo-5-nitrobenzoic acid (15.48 g, 52.83 mmol) and Pd (Ph3P) 4 (1.84 g, 1.69 mmol) in 300 ml of toluene and 50 ml of ethanol were added p-tolylboronic acid (7.87 g, 58.11 mmol) and a solution of CS2CO3 (18.89 g, 58 , 11 mmols) in 20 ml water in RT. The reaction was brought to reflux for 18 hours and then cooled to RT. To the solution, 2N NaOH was added, and the reaction mixture was stirred for 30 minutes. The organic phase was separated, and the aqueous phase was adjusted to pH <4 using 12N HCI. The resulting solid precipitate was filtered and washed with toluene to provide 13.2 g of 4'-methyl-5-nitro-biphenyl-3-carboxylic acid as a light yellow solid (97.2%). MS (M + H) = 258.

STEP 3 4-METHYL-5-NITROBYphenyl-3-CARBOXYLIC ACID AMID (2-METHYX-1-METHYL-ETHYL) [000421] EDCI (16.17 g, 84.38 mmol) was added in portions to one stirred solution of 4'-methyl-5-nitro-biphenyl-3-carboxylic acid (15.49 g, 60.27 mmol), HOBt (11.44 g, 84.38 mmol) and 2-amino-1-methoxy -1-propane (7 ml, 66.31 mmols) in NMP (9.29 ml, 84.38 mmols), CH2 Cl2 (180 ml) and DMF (20 ml) at 0Ό. The mixture was allowed to warm to RT and was stirred at the same temperature for 14 hours. The reaction mixture was washed with 2N HCI, 2N NaOH, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give acid (2-methoxy-1-methyl-ethyl) -amide 4 '-methyl-5-nitro-biphenyl-3-carboxylic as a yellow oil (16.5 g, 83.5%). MS (M + H) = 329.

STEP 4 (2-METHOXY-1-METHYL-ETHYL) -AMID OF 5-AMINO-4'-METHYLBYphenyl-3-CARBOXYLIC ACID [000422] To a stirred solution of (2-methoxy-1-methyl-ethyl) -amide of 4'-methyl-5-nitro-biphenyl-3-carboxylic acid (39 mmols) in 250 ml of methanol, SnCL (117 mmols) was added in one portion at RT. The reaction mixture was heated to reflux for 3 hours. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and treated with saturated NaHCO3 solution. Solids were filtered and the filtrate was washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and

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71/98 vacuum concentrated to give 5 amino-4'- methyl-biphenyl-3- carboxylic acid (2-methoxy-1-methyl-ethyl) -amide as a yellow oil (10.5g, 90.3%). MS (M + H) = 299.

STEP 5 (2-METHOXY-1-METHYL-ETHYL) -ACID ACID 5-IODO-4'-METHYLBIPHENYL-3-CARBOXYLIC [000423] A mixture of (2-methoxy-1-methyl-ethyl) -amide 5-amino4'-methyl-biphenyl-3-carboxylic (5.3 g, 17, 8 mmols), iso-amyl nitrite (13.5 ml, 88.9 mmols) and di-iodomethane (8 ml, 106, 7 mmols) was stirred at RT for 1 hour. The mixture was then heated to 650 and held for 8 hours, LC / MS indicated that the reaction was complete. The reaction mixture was cooled to RT and the separation of excess iodobenzene diiododomethane was performed by adding the reaction mixture in RT to a stirred solution of piperidinCH3CN (V / V = 90ml / 90ml). A vigorous exothermic reaction resulted. Excess volatile reagents were removed by rotary evaporation at 80Ό. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water and brine. The organic layer was separated and dried over anhydrous Na ₂ SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / hexanes = 10: 1) to yield 5-iodo-4'-methyl-biphenyl-3 (2-methoxy-1-methyl-ethyl) -amide -carboxylic as a yellow solid (5.2 g, 83.8%). MS (M + H) = 410.

[000424] Similarly prepared, using the appropriate amine compound in step 3, were:

5-sludge-4'-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl) -amide, MS (M + H) = 444;

5-sludge-4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide, MS (M + H) = 396;

5-sludge-4'-methyl-biphenyl-3-carboxylic acid (1-methyl-2-morpholin-4-yl-ethyl) -MS, MS (M + H) = 465;

[2- (1,1-dioxide-1lambda * 6 * -thiomorpholin-4-yl) -1-methyl-ethyl] -amide of 5-sludge4'-methyl-biphenyl-3-carboxylic acid, MS (M + H ) = 513; and 5-sludge-4'-methyl-biphenyl-3-carboxylic acid (pyrazin-2-ylmethyl) -amide, MS (M + H) = 430.

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PREPARATION 6: 5-IODO-4'-METHYL-BYPHENYL-3-CARBOXYLIC ACID [000425] The synthetic procedure used in this preparation is outlined below in Scheme H.

ESQUEMAH

STEP 1 4'-METHYL-5-NITRO-BYPHENYL-3CARBOXYLIC ACID METHYL ESTER [000426] To a solution of 4'-methyl-5-nitro-biphenyl-3-carboxylic acid (10.00 g, 0.039 mol) in methanol was added SOCI2 (5.09 g, 0.043 mol) at 0Ό. The reaction mixture was allowed to warm to T A and was then heated to reflux for 2 hours. The solvent was removed in vacuo to yield 4'-methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester (9.72 g, 92%) as a light yellow solid. MS (M + H) = 273.

STEP 2 5-AMINO-4'-METHYL-BIPhenyl-3CARBOXYLIC ACID METHYL ESTER [000427] 4'-Methyl-5-nitro-biphenyl-3-carboxylic acid methyl ester was reduced using SnCL using the procedure from step 4 of preparation 6 to yield 5-amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester, MS (M + H) = 242.

STEP 3 5-IODO-4'-METHYL-BIPHENYL-3CARBOXYLIC ACID METHYL ESTER [000428] 5-Amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester was treated with methylene iodide and isoamyl nitrate using the procedure of step 5 of preparation 5, to yield 5-iodo-4'-methyl-biphenyl-3 acid Petition 870180137880, of 10/04/2018, p. 85/114

73/98 carboxylic, MS (M + H) = 353.

[000429] Similarly prepared was 2'-fluoro-5iodo-4'-methyl-biphenyl-3-carboxylic acid methyl ester, MS (M + H) = 371.

PREPARATION 7: 3-IODO-5- (5-METHYL-PYRIDIN-2-IL) -BENZOIC ACID [000430] The synthetic procedure used in this preparation is outlined below in Scheme I.

SCHEME I

STEP 1 3-IODO-5-NITRO-BENZOIC ACID METHYL ESTER [000431] To a solution of 3-iodo-5-nitrobenzoic acid (20.00 g, 0.068 mol) in methanol (50 ml) was added SOCL (5 , 45 ml, 0.075 mol) at 0Ό. The reaction mixture was allowed to warm to RT and then heated under reflux for 2 hours. The reaction was cooled and the solvent was removed in vacuo to provide 3-sludge-5-nitro-benzoic acid methyl ester as a light yellow solid (20.67 g, 99%). MS (M + H) = 309.

STEP 2 3-NITRO-5- (4,4,5,5-TETRAMETHYL [1,3,2] DIOXABOROLAN-2-IL) -BENZOIC ACID METHYL ESTER [000432] A 3-iodine acid methyl ester solution -5-nitro-benzoic

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74/98 (10 g, 0.0326 mol), bis (pinacolate) diboro (9.1 g, 0.0358 mol), KOAc (9.5 9g, 0.098 mol) and PdCl2 (dppf) (798 mg, 0 , 98 mmol) in DMSO (40 ml) was heated to 80Ό for 4 hours under N 2 atmosphere. The mixture was cooled to RT and extracted with Et20. The combined organic phases were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the resulting 3-nitro-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzoic acid methyl ester was used without purification in the next step.

STEP 3 3- (5-METHYL-PYRIDIN-2-IL) -5-NITROBENZOIC ACID METHYL ESTER [000433] To a solution of 2-bromo-5-methylpyridine (1.24 g, 7 mmols), Pd (PPh ₃ ) ₄ (226 mg, 0.2 mmol) and KsPO4 (2.76 g, 13 mmol) in DME / H2O (5 ml / 1 ml) 3-nitro-5- acid methyl ester (4.4 , 5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -benzoic acid (2.00 g, 6.5 mmols) under N2 atmosphere. The mixture was subjected to microwave radiation at 130Ό for 0.5 hours. The reaction mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (ChLCh / MeOH) to give 3- (5-methyl-pyridin-2-yl) -5-nitro-benzoic acid methyl ester as a white solid (700 mg, 40%).

STEP 4 3-AMINO-5- (5-METHYL-PYRIDIN-2IL) -BENZOIC ACID METHYL ESTER [000434] To a solution of 3- (5-methyl-pyridin-2-yl) 5-nitro acid methyl ester -benzoic acid (4 g, 14.7 mmols) in methanol / ethyl acetate SnCb (11.15 g, 58.8 mmols) was added in RT. The reaction mixture was refluxed for 3 hours and then cooled. Solvent was removed under reduced pressure and the residue was dissolved in H2O and basified by adding Na2CO ₃ to pH = 9. The mixture was extracted with CH2Cl2, and the organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give 3-amino-5- (5-methyl-pyridin-2-yl) -benzoic acid methyl ester (3.2g, 90%) as a white solid.

STEP 5 3-IODINE-5- (5-METHYL-PYRIDIN-2-IL) BENZOIC ACID METHYL ESTER

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75/98 [000435] 5- (5-Methyl-pyridin-2-yl) -benzoic acid methyl ester was treated with methylene iodide and isoamyl nitrate using the procedure from step 5 of preparation 6, to provide methyl ester of 3-iodo-5- (5-methylpyridin-2-yl) -benzoic acid, MS (M + H) = 353.

STEP 6 3-IODO-5- (5-METHYL-PYRIDIN-2-IL) -BENZOIC ACID [000436] A solution of LiOH hydrate (82 mg, 1.94 mmol) in H2O (7 ml) was added dropwise to a suspension of 3-iodo-5- (5-methyl-pyridin-2-yl) -benzoic acid methyl ester (526 mg, 1.49 mmol) in THF (4 ml) at 0 °. The reaction mixture was allowed to warm to T A and was stirred until the reaction solution was clear. Solvent was removed in vacuo and the resulting aqueous solution was acidified by 10% HCl at pH = 6 ~ 7. The resulting precipitate was collected and dried to provide 3-iodo-5- (5-methyl-pyridin-2yl) -benzoic acid (470 mg, 93%). MS (M + H) = 340.

[000437] Similarly prepared, but using 2-bromo-5-chloropyridine in step 3 instead of 2-bromo-5-methylpyridine, was 3-iodo-5- (5-chloropyridin-2-yl) -benzoic acid, MS (M + H) = 360.

PREPARATION 8: 3-BROMO-5- (5-METHYLPYRIDIN-2-IL) -BENZOIC ACID METHYL ESTER [000438] The synthetic procedure used in this preparation is outlined below in Scheme J.

SCHEME

STEP 1 3-BROMO-5- (4,4,5,5-TETRAMETHIL- [1,3,2] DIOXABOROLAN-2-IL) -BENZOIC ACID METHYL ESTER [000439] 3-Bromo-5 acid methyl ester -iodo-benzoic (14.16 g, 41.53 mmols), bis (pinacolate) -diborane (11.60 g, 45.7 mmols), PdCÍ2 (dppf) 2 (1.02 g, 1.256 mmol) and acetate potassium (12.22 g, 124.6 mmols) were added to 50 ml of DMSO, and the reaction mixture was stirred at 80Ό for 20 hours, then cooled to RT. The reaction mixture was diluted with water and

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76/98 extracted with diethyl ether. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give 18.5 g of 3-bromo-5- (4,4,5,5-tetramethyl- [1,3,2) methyl ester ] dioxaborolan2-yl) -benzoic acid which was used directly in the next step without further purification.

STEP 2 3-BROMO-5- (5-METHYL-PYRIDIN-2IL) -BENZOIC ACID METHYL ESTER [000440] A mixture of 2-bromo-5-methyl-pyridine (10.27 g, 59.68 mmols) and tetrakis (triphenylphosphine) palladium (1.88 g, 1.65 mmol) in 300 ml DME was stirred at 60Ό under nitrogen for 30 minutes. To this mixture was added 3-bromo-5- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzoic acid methyl ester (18.5 g, 54.25 mmols), followed by K3PO4 (23.03 g, 108.5 mmols) in 40 ml of water. The mixture was refluxed for eight hours, then cooled to RT and divided between water and EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5: 1 EtOAc / hexanes) to give 8.5 g of 3-bromo-5- (5methyl-pyridin-2-yl) -benzoic acid methyl ester, MS (M + H) = 306.

[000441] Similarly prepared were:

3-Bromo-5- (2-chloro-5-methyl-pyridin-2-yl) benzoic acid methyl ester, MS (M + H) = 341;

3-Bromo-5- (2-fluoro-5-methyl-pyridin-2-yl) benzoic acid methyl ester, MS (M + H) = 325; and

3-Bromo-5- (5-chloro-pyridin-2-yl) -benzoic acid methyl ester, MS (M + H) = 327.

EXAMPLE 1: 4'-METHYL-5 [1,2,3] TRIAZOL-1-IL-BIPENYL-3-CARBOXYLIC ACID (2-METHYXY-1-METHYL-ETHYL) [000442] The synthetic procedure used in this preparation is outlined below in Scheme K.

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STEP 1 (2-METHOXY-1-METHYL-ETHYL) -AMID OF 5-AZIDO-4'-METHYLBIPHENYL-3-CARBOXYLIC ACID [000443] To a solution of (2-methoxy-1-methyl-ethyl) -amide of 5 amino-4'- methyl-biphenyl-3- carboxylic acid (500 mg, 1.68 mmol) in trifluoroacetic acid (10 ml) was added a solution of NaNO2 (21.47 mmols, 1.49 g) in water (10 mL) at 0Ό. The mixture was stirred at 0Ό for 10 minutes and a solution of NaN3 (44.43 mmols, 2.89g) in water (10 ml) was added. The solution was stirred at RT for 16 hours. Solvent was removed under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 5-azido-4'-methyl-biphenyl-3-carboxylic Acid (2-methoxy-1-methylethyl) -amide. (80%). MS (M + H) = 325.

STEP 2 4-METHYL-5- [1,2,3] TRIAZOL-1-IL-BYPHENYL-3-CARBOXYLIC ACID (2-METHODY-1-METHYL-ETHYL) [000444] A solution of (2 -methoxy-1-methyl-ethyl) -amide of 5-azido4'-methyl-biphenyl-3-carboxylic acid (488 mg, 1.5 mmol), ethinyltrimethylsilane (4.5 mmols, 0.64 ml) in DMF ( 6 ml) was heated to 110Ό for 16 hours. The mixture was cooled and filtered, and the filtrate was purified by preparative HPLC

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78/98 to provide 262 mg 4'-methyl-5 [1,2,3] triazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide as a white solid (50%). MS (M + H) =

351.

[000445] Additional compounds prepared by the above procedure are shown in Table 1.

EXAMPLE 2: 4'-METHYL-5 [1,2,3] TRIAZOL-2-IL-BYPHENYL-3-CARBOXYLIC ACID (2-METOXY-1-METHYL-ETHYL) [000446] The synthetic procedure used in this preparation is outlined below in Scheme L.

SCHEME

STEP 1 5-HYDRAZINO-4'METHYL-BIPhenyl-3-CARBOXYLIC ACID AMID (2-METHYXY-1-METHYL-ETHYL) [000447] (5- 2-methoxy-1-methyl-ethyl) -amide acid 5- amino-4'-methyl-biphenyl-3-carboxylic (596 mg, 2 mmol) was dissolved in 6 ml of concentrated HCl and stirred for 15 minutes at 0 °. To the reaction mixture, a solution of NaNO2 (138 mg, 2 mmols) in water (1.5 ml) was added dropwise at 0Ό. The mixture was stirred for 30 minutes, and then a solution of SnCl2 (4.5 mmols, 189.6 mg) in 2 ml of concentrated HCl was added dropwise. A precipitate started to form immediately. After stirring for

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79/98 minutes, the resulting 5-hydrazino-4'-methylbiphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide was isolated as a hydrochloride salt by filtration and immediately used in the next step .

STEP 2 4-METHYL-5- [1,2,3] TRIAZOL-2-IL-BYPHENYL-3-CARBOXYLIC ACID (2-METHODY-1-METHYL-ETHYL) [000448] A salt mixture 5-hydrazino-4'-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide hydrochloride (2 mmols), glyoxal (40% aqueous solution, 1 ml) and 50% aqueous acetic acid (2 ml) was heated to 150Ό for 60 minutes by microwave irradiation. The reaction mixture was cooled and diluted with EtOAc, washed with saturated aqueous Na2CO3, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 210 mg of 4'-methyl-5- [1,2,3] triazol-2-yl-biphenyl-3-carboxylic acid (2methoxy-1-methyl-ethyl) -amide as a white solid (30%). MS (M + H) = 351.

[000449] Additional compounds prepared by the above procedure are shown in Table 1.

EXAMPLE 3: 5- (5-ISOPROPIL [1,2,4] TRIAZOL-1-IL) -4'-METHYL-BIPhenyl-3-CARBOXYLIC ACID (1-PIRAZIN-2-IL-ETHYL) -000450 ] The synthetic procedure used in this preparation is outlined below in Scheme M.

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STEP 1 5- (5-ISOPROPIL- [1,2,4] TRIAZOL-1IL) -4'-METHYL-BIPhenyl-3-CARBOXYLIC ACID METHYL ESTER [000451] 5-Hydrazino-4'- acid methyl ester methyl-biphenyl-3-carboxylic used in this Example was prepared from 5-amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester following the procedure of step 1 of Example 6. [000452] To a methyl ester solution of 5-hydrazino-4'-methylbiphenyl-3-carboxylic acid (300 mg, 1.17 mmol) in HOAc (5 ml) Ndimethylaminomethylene-isobutyramide (233 mg, 1.4 mmol) was added in one portion. The mixture was heated to 90Ό for two hours. After removing excess HOAc, the residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®) to yield 5- (5-isopropyl [1,2,4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid methyl ester as a yellow solid (293 mg, 74.6%).

STEP 2 ACID 5- (5-ISOPROPIL- [1,2,4] TRIAZOL-1-IL) -4'-METHYL-BIPENYL3-CARBOXYLIC [000453] 5- (5-lsopropyl- [1,2] methyl acid ester , 4] triazol-1-yl) -4'-methylbiphenyl-3-carboxylic acid was hydrolyzed with LiOH following the procedure of step 2, Example 8, to give 5- (5-lsopropyl- [1,2,4] triazole acid -1-yl) -4'-methylbiphenyl-3-carboxylic.

STEP 3 (1-PIRAZIN-2-IL-ETHYL) -ACID ACID 5- (5-ISOPROPIL- [1,2,4]

TRIAZOL-1-IL) -4'-METHYL-BIPHYENIL-3-CARBOXYLIC [000454] 5- (5-Lsopropyl- [1,2,4] triazol-1-iI) -4'-methyl-biphenyl-3 acid -carboxylic acid was subjected to the amide coupling reaction described in step 4 of

Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5- (5-isopropyl- [] acid (1-pyrazin-2-yl-ethyl) -amide 1.2.4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic, MS (M + H) = 427.

[000455] Similarly prepared, but replacing 5-hydrazino-4'-methyl-biphenyl-3-carboxylic acid methyl ester in step 1 with 3-hydrazino-5- (5-methyl-pyridin-2-yl) methyl ester ) -benzoic acid (prepared as described in step 1 of Example 6), was 3- (5-isopropyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyriPetition 870180137880, from 04 / 10/2018, page 93/114

81/98 din-2-yl) -N- (1-pyrazin-2-yl-ethyl) -benzamide, MS (M + H) = 428.

EXAMPLE 4: 5- [5- (1-METHODYL) ACID (1-PIRAZIN-2-IL-ETHYL) - [1,2,4] TRIAZOL-1 -IL] -4'-METHYL-BIPHYL -3-CARBOXYLIC [000456] The synthetic procedure used in this preparation is outlined below in Scheme N.

ESQUEMAN

h ₃ c

STEP 1 5- [5- (1-HYDROXY-ETHYL) - [1,2,4] TRIAZOL-1-IL] -4'-METHYL-BIPhenyl-3-CARBOXYLIC ACID METHYL [000457] A mixture of 2 -hydroxy-propionamide (1.0 g, 11.2 mmols) and N, N-dimethylformamide dimethyl acetal (1.06 g, 8.96 mmols) in dimethyl glycol (6 ml) was heated to 80Ό for two hours , then cooled to TA. Mixture T was added to a solution of 5hydrazino-4'-methyl-biphenyl-3-carboxylic acid methyl ester (1.2 g, 4.1 mmol) in HOAc (5 ml), and the mixture was heated to 80Ό by two other hours. The reaction mixture was cooled and the volatiles were removed under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to yield 5- [5- (1-hydroxyethyl) - [1,2,4] triazol-1-yl] -4' methyl ester Petition 870180137880, 10/04 / 2018, p. 94/114

82/98 methyl-biphenyl-3-carboxylic as a white solid (410 mg, 29.76%).

STEP 2 5- [5- (1-METOXY-ETHYL) - [1,2,4] TRIAZOL-1-IL] -4'-METHYL-BIPhenyl-3-CARBOXYLIC ACID METHYL [000458] To a mixture of 5- [5- (1-hydroxy-ethyl) - [1,2,4] triazole-1-yl] -4'4methyl-biphenyl-3-carboxylic acid methylester suspension (300 mg, 0.89 mmol) and Ag2Ü (454 mg, 1.96 mmol) in CH3CN (5 ml) Honey (1 ml) was added. The reaction mixture was wrapped with alumina foil and stirred overnight. The solid was filtered and washed with CH3CN. The combined filtrate was condensed and the residue was purified by ISCO to yield 5- [5- (1-methoxy-ethyl) - [1,2,4] triazole-1-yl] -4'-methyl- biphenyl-3-carboxylic as a light yellow solid (290 mg, 93.0%).

STEP 3 ACID 5- [5- (1-METHYXY-ETHYL) - [1,2,4] TRIAZOL-1 -IL] -4'-METI L-BIPENYL-3-CARBOXYLIC [000459] 5- Acid methyl ester [5- (1-Methoxy-ethyl) - [1,2,4] triazol-1-yl] -4'methyl-biphenyl-3-carboxylic was hydrolyzed with LiOH following the procedure of step 2, Example 8, to give 5- [5- (1-methoxy-ethyl) - [1,2,4] triazol-1-yl] 4'-methyl-biphenyl-3-carboxylic acid.

STEP 4 (1-PIRAZIN-2-IL-ETHYL) -ACID ACID 5- [5- (1-METHYXY-ETHYL) [1.2.4] TRIAZOL-1-IL] -4'-METHYL-BIPHYL-3- CARBOXYLIC [000460] 5- [5- (1-Methoxy-ethyl) - [1,2,4] triazol-1-yl] -4'-methyl-biphenyl-3-carboxylic acid was subjected to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-ylethylamine, to give 5- [5- (5-) 5- acid (1-pyrazin-2-yl-ethyl) -amide (1-methoxy-ethyl) [1.2.4] triazol-1-yl] -4'-methyl-biphenyl-3-carboxylic, MS (M + H) = 443.

[000461] Similarly prepared, but replacing 5-hydrazino-4'-methyl-biphenyl-3-carboxylic acid methyl ester in step 1 with 3-hydrazino-5- (5-methyl-pyridin-2-yl) methyl ester ) -benzoic acid (prepared as described in step 1 of Example 6), was 3- [5- (1-Methoxy-ethyl) - [1,2,4] triazole-1-yl] -5- (5-methylpyridin- 2-yl) -N- (1-pyrazin-2-yl-ethyl) -benzamide, MS (M + H) = 444.

EXAMPLE 5: 5- (5-ISOPROPIL [1,2,3] TRIAZOL-1-IL) -4'-METHYL-BIPENYL-3-CARBOXYLIC ACID (1-PIRAZIN-2-IL-ETHYL) -000562 ] The synthetic procedure used in this preparation is outlined

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83/98 below in Scheme O. SCHEME O

ch ₃

STEP 1 5-ISOPROPYL-1- (5-METOXICARBONYL-4'-METHYL-BIPHYL-3-IL) -1 H- [1,2,3] TRIAZOL-4-CARBOXYLIC ACID ETHYL ESTER [000463] The methyl ester of 5-azido-4'-methyl-biphenyl-3-carboxylic acid used in this step was prepared from 5-amino-4'-methylbiphenyl-3-carboxylic acid methyl ester using the procedure of step 1 of Example 4. [000464 ] To a mixture of 5-azido-4'-methyl-biphenyl3-carboxylic acid methyl ester (200 mg, 0.75 mmol) and ethyl isobutyrylacetate (119 mg, 0.75 mmol) in EtOH (5 ml) EtONa (51 mg, 0.75 mmol) is added and the mixture was heated to 80 ° for two hours, then cooled to RT. EtOH was removed from the reaction mixture to yield 5isopropyl 1-1 - (5-methoxycarbonyl-4'-methyl-biphenyl-3-yl) -1 H- [1,2,3] triazole-4-carboxylic acid ethyl ester as a gel that was directly used in the next step.

STEP 2 ACID 1- (5-CARBoxy-4'-METHYL-BIPHYEN-3-IL) -5-ISOPROPIL-1 HPetition 870180137880, of 10/04/2018, p. 96/114

84/98 [1,2,3] TRIAZOL-4-CARBOXYLIC [000465] The ethyl ester of 5-isopropyl-1- (5-methoxycarbonyl-4'-methylbiphenyl-3-yl) -1 H- [1 , 2,3] triazole-4-carboxylic step 1 was dissolved in THF (7 ml) and water (4 ml) and LiOH.H2O (184 mg, 4.38 mmol) was added as a single portion. The reaction mixture was stirred at RT for three hours. Solvent was removed under reduced pressure and the remaining aqueous solution was acidified with concentrated HCl to pH ~ 1. The solution was extracted with EtOAc and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1 - (5-carboxy-4'-methyl-bipheni l-3-yl) - 5-isopropyl 1-1 H- [1,2,3] triazole-4-carboxylic light yellow solid (260 mg) which was used without further purification in the next step.

STEP 3 5- (5-ISOPROPIL- [1,2,3] TRIAZOL-1-IL) -4'-METHYL-BIPHYLENE3-CARBOXYLIC ACID [000466] 1 - (5-Carboxy-4'-methyl-biphenyl acid) -3-iI) -5-isopropyl 1-1 H- [1,2,3] triazole-4-carboxylic from step 2 was heated to 170 ° C until no more carbon dioxide was released. The reaction mixture was cooled to RT, and the resulting crude 5- (5-lsopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid was directly used in the next step without further purification. STEP 4 (1-PIRAZIN-2-IL-ETHYL) -ACID ACID 5- (5-ISOPROPIL- [1,2,3] TRIAZOL-1-IL) -4'-METHYL-BIPhenyl-3-CARBOXYLIC [000467 ] 5- (5-lsopropyl- [1,2,3] triazol-1-iI) -4'-methyl-biphenyl-3-carboxylic acid was subjected to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5- (5-isopropyl- [1,2, 1-pyrazin-2-yl-ethyl) -amide 3] triazol1 -yl) -4'-methyl-biphenyl-3-carboxylic, MS (M + H) = 427.

EXAMPLE 6: 3- (5-ISOPROPIL- [1,2,4] TRIAZOL-1 -IL) -N- (5-METIL-PIRAZIN2-ILMETIL) -5- (5-METYL-PIRIDIN-2-IL) - BENZAMIDA [000468] The synthetic procedure used in this preparation is outlined below in Scheme P.

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Step 4

STEP 1 3-HYDRAZINE-5- (5-METHYL-PYRIDIN2-IL) -BENZOIC ACID METHYL ESTER [000469] 3-Amino-5- (5-methyl-pyridin-2-yl) -benzoic acid methyl ester ( 1.0 g, 4 mmols) was suspended in 16 ml of concentrated aqueous HCI, and the mixture was cooled to 0Ό. A solution of sodium nitrite (0.30 g) in water (3 ml) was added, and the mixture was stirred at 0 ° for 45 minutes. A solution of SnCL hydrate (2.34 g) in 5 ml of concentrated aqueous HCI was then added. The reaction mixture was stirred for one hour in RT, then filtered. The collected solid was washed with water and dried to give 1.80 g of 3-hydrazino-5- (5-methyl-pyridin-2-yl) -benzoic acid methyl ester as a white powder.

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STEP 2 3- (5-ISOPROPIL- [1,2,4] TRIAZOL-1IL) -5- (5-METHYL-PYRIDIN-2-IL) -BENZOIC ACID METHYL ESTER [000470] Isobutyramide (6.02 g, 69 mmols) and DMFDMA (9.22 ml) were added to 10 ml of DMA in a first flask, and the mixture was heated to 80Ό with stirring for one hour. In a second flask, a suspension of 3-hydrazino-5- (5-methyl-pyridin-2-yl) -benzoic acid methyl ester (6.42 g, 23 mmols) was suspended in acetic acid and heated to 800. The contents of the first flask were slowly added to the second flask, and the combined mixture was stirred at 800 for two hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water, dried (MgSCU), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes / EtOAc 4: - 2: 1) to give 2.06 g of 3- (5-isopropyl- [1,2,4] triazol-1-yl acid methyl ester ) -5- (5-methyl-pyridin2-yl) -benzoic acid as a clear oil, MS (M + H) = 337.

STEP 3 ACID 3- (5-ISOPROPIL- [1,2,4] TRIAZOL-1-IL) -5- (5-METHYL-PIRIDIN-2-IL) -BENZOIC [000471] 3- (5) Methyl ester -lsopropyl- [1,2,4] triazol-1-yl) -5- (5-methyl-pyridin-2-yl) -benzoic acid (2.0 g, 6 mmol) was dissolved in 30 ml of MeOH, and 2.0 ml of 3N aqueous NaOH was added. The reaction mixture was stirred at RT for 18 hours, then cooled and acidified with 10% aqueous HCI, and concentrated under reduced pressure to yield 2.45 g of acid 3 (5-isopropyl- [1,2,4] triazole -1 -yl) -5- (5-methyl-pyridin-2-yl) -benzoic.

STEP 4 3- (5-ISOPROPIL- [1,2,4] TRIAZOL-1 -IL) -N- (5-METYL-PIRAZIN-2YLMETHY) -5- (5-METYL-PIRIDIN-2-IL) -BENZAMIDE [000472] 3- (5-lsopropyl- [1,2,4] triazol-1-iI) -5- (5-methyl-pyridiη-2-iI) -benzoic acid (1.90 g, 6 mmols), C- (5-methyl-pyrazin-2-yl) -methylamine (0.73 g, 6 mmols), EDCI (1.69 g, 9 mmols), HOBt (1.20 g, 9 mmols) and NMM (3 , 2 ml) were added to 20 ml of acetonitrile. The reaction mixture was stirred at RT for 18 hours under a nitrogen atmosphere, then divided between water and EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by means of

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87/98 flash chromatography (IPA / DCM 1: 4)) to give 1.63 g of 3- (5-isopropyl [1,2,4] triazol-1-yl) -N- (5-methyl-pyrazin -2-ylmethyl) -5- (5-methyl-pyridin-2-yl) benzamide, MS (M + H) = 428.

EXAMPLE 7: N- (5-METHYL-PIRAZIN-2-ILMETHIL) -3- (5-METHYL-PYRIDIN-2-IL) -5 (5-TRIFLUOROMETHIL- [1,2,4] TRIAZOL-1 -IL) -BENZAMIDA [000473] The synthetic procedure used in this preparation is outlined below in Scheme Q.

SCHEMEQ

STEP 1 N- (5-METHYL-PYRIDIN-2-IL) -5- (5TRIFLUOROMETHIL- [1,2,4] TRIAZOL-1 -IL) -BENZOIC ACID METHYL ESTER [000474] Trifluoroacetamide (4.70g, 40 mmols) was dissolved in 15 ml of DME in a first flask, and 5.53 ml of DMF DMA were added. The mixture was stirred at RT for 30 minutes, and then the solvent was removed under reduced pressure. In a second flask, toluene sulfonic acid (11.85 g, 60 mmols) and 3-hydrazino-5- (5-methyl-pyridin-2yl) -benzoic acid methyl ester (6.08 g, 20 mmols) were dissolved in 100 ml of DMSO and heated to 70Ό. The contents of the first flask were added to the contents of the second flask, and the reaction mixture was stirred at 700 ° C for two hours. The reaction mixture was cooled to RT and partitioned between water and EtOAc. The combined organic layers were washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 1.44 g of ester

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88/98 N- (5-methyl-pyridin-2-yl) -5- (5-trifluoromethyl- [1,2,4] triazol-1-yl) benzoic acid methyl as a white solid, MS (M + H) = 363.

STEP 2 N- (5-METHYL-PYRIDIN-2-IL) ACID -5- (5-TRIFLUOROMETHIL- [1,2,4] TRIAZOL-1 -IL) -BENZOIC [000475] N- (5) Methyl ester -methyl-pyridin-2-yl) -5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -benzoic acid (1.44 g) was dissolved in a mixture of MeOH and THF (20 ml of each) along with 2 ml of 3N aqueous NaOH. The mixture was stirred 18 hours in RT, then cooled to OO and acidified with 10% aqueous HCI to a pH of about 4. The solvent was removed under reduced pressure to give 1.50 N- (5-methyl-pyridin acid) -2-yl) -5- (5-trifluoromethyl [1,2,4] triazol-1-yl) -benzoic acid as a white solid.

STEP 3 N- (5-METIL-PIRAZIN-2-ILMETIL) -3- (5-METIL-PYRIDIN-2-IL) -5- (5TRIFLUORO METIL- [1,2,4] TRIAZOL-1 -IL) - BENZAMIDE [000476] N- (5-methyl-pyrazin-2-ylmethyl) -3- (5-methyl-pyridin-2-yl) -5- (5-trifluoromethyl- [1,2,4] triazole-1- il) -benzamide (670 mg, MS (M + H) = 454) was prepared from N- (5-methyl-pyridin-2-yl) -5- (5-trifluoromethyl- [1,2,4] triazole acid -1-yl) -benzoic and C (5-methyl-pyrazin-2-yl) -methylamine using the procedure from step 6 of Example 6.

EXAMPLE 8: 5- (3-ISOPROPYL-5-METHYL- [1,2,4] TRIAZOL-4-IL) -4'-METHYL-BYphenyl-3- ACID (1-PIRAZIN-2-IL-ETHYL) CARBOXYLIC [000477] The synthetic procedure used in this preparation is outlined below in Scheme R.

SCHEME

Step 2

NaOH

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STEP 1 5- (3-ISOPROPYL-5-METHYL- [1,2,4] TRIAZOL-4-IL) -4'-METHYL-BYphenyl-3-CARBOXYLIC ACID METHYL [000478] The used isobutyric acid hydrazide in this example wasobutyric acid chloride and hydrazine hydrate were prepared following the procedure of Org. Synth. Vol. 81 p. 254 (2005).

[000479] Isobutyric acid hydrazide (55 mg, 5.34 mmols) and 1,1-dimethoxy-ethyl) -dimethyl-amine (774 mg, 5.81 mmols) were added to 6 ml of CH3CN and the mixture was heated to 50Ό and stirred for 30 minutes. 5-Amino-4'-methyl-biphenyl-3-carboxylic acid methyl ester (1.0 g, 4.15 mmol) was added, followed by 6 ml of acetic acid. The reaction mixture was heated to 120Ό and stirred for five hours, then cooled to RT. Solvent was removed under reduced pressure and the residue was purified by flash chromatography to give 400 mg (30%) of 5- (3-lsopropyl-5-methyl- [1,2,4] triazole-4-methyl ester) -yl) -4'-methyl-biphenyl-3-carboxylic as a white powder.

STEP 2 5- (3-ISOPROPYL-5-METHYL- [1 ^. ^ TRIAZOL ^ -ILK-METHYLBYphenyl-S-CARBOXYLIC ACID [000480] 5- (3-Lsopropyl-5-methyl- [1,2,4) acid ] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid was prepared by basic hydrolysis of 5- (3-lsopropyl-5-methyl- [1,2,4] triazol-4-yl acid methyl ester ) -4'-methyl-biphenyl-3-carboxylic following the procedure of step 3 of Example 4.

STEP 3 (1-PIRAZIN-2-IL-ETHYL) -ACID ACID 5- (3-ISOPROPYL-5METHYL- [1,2,4] TRIAZOL-4-IL) -4'-METHYL-BYphenyl-3-CARBOXYLIC [000481] 5- (3-lsopropyl-5-methyl- [1,2,4] triazol-4-yl) -4'-methyl-biphenyl- (1-pyrazin-2-yl-ethyl) -amide 3-carboxylic acid was prepared from 5- (3-isopropyl-5methyl- [1,2,4] triazol-4-yl) -4'-methyl-biphenyl-3-carboxylic acid and 1-pyrazin-2-yl-ethylamine using the procedure from step 4 of Example 6.

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EXAMPLE 9: FORMULATIONS [000482] Pharmaceutical preparations for delivery by various routes are formulated as shown in the following Tables. Active ingredient or Active compound as used in the Tables means one or more of the Compounds of formula I.

COMPOSITION FOR ORAL ADMINISTRATION

Ingredient % p./p. Active ingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

[000483] The ingredients are mixed and dispensed in capsules containing about 100 mg each; a capsule would approach a total daily dosage.

COMPOSITION FOR ORAL ADMINISTRATION

Ingredient % p./p. Active ingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0% Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

[000484] The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and tableted (containing about 20 mg of active compound) with an appropriate tablet machine.

COMPOSITION FOR ORAL ADMINISTRATION

Ingredient Amount Active compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g Propyl Paraben 0.05 g

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Ingredient Amount Granulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Condiment 0.035 ml Colorings 0.5 mg Distilled water q.s. to 100 ml

[000485] The ingredients are mixed to form a suspension for oral administration.

[000486] PARENTERAL FORMULATION

Ingredient % p./p. Active ingredient 0.25 g Sodium chloride qs to make isotonic Water for injection 100ml

[000487] The active ingredient is dissolved in a portion of the water for injection. A sufficient amount of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up by weight with the rest of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

SUPPOSITORY FORMULATION

Ingredient % p./p. Active ingredient 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

[000488] The ingredients are melted and mixed in a steam bath, and poured into molds containing 2.5 g of total weight.

TOPICAL FORMULATION

Ingredients Grams Active compound 0.2-2 Span 60 2 Tween 60 2

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Ingredients Grams Mineral oil 5 Petrolato 10 Methyl paraben 0.15 Propyl Paraben 0.05 BHA (butylated anisole hydroxy) 0.01 Water q.s. 100

[000489] All ingredients, except water, are combined and heated to about 60Ό with stirring. A sufficient amount of water in about 60Ό is then added with vigorous stirring to emulsify the ingredients, and water is then added q.s. about 100 g. NASAL SPRAY FORMULATIONS [000490] Various aqueous suspensions containing about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, and the like. Hydrochloric acid can be added to adjust the pH. Nasal spray formulations can be delivered using a metered nasal spray pump typically releasing about 50100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

EXAMPLE 10: FLIPR ASSAY P2X ₃ / P2X _2/3 (The reader IMAGING PLATE fluorometric) [000491] CHO-K1 cells were transfected with subunits of P2X ₃ receptors rat or P2X _2/3 human cloned and passed on bottles. 18-24 hours before the FLIPR experiment, the cells were released from their flasks, centrifuged, and resuspended in nutrient medium at 2.5 x 105 cells / ml. The cells were aliquoted in 96-well plates with a black wall at a density of 50,000 cells / well and incubated overnight in 5% CO ₂ at 37Ό. On the day of the experiment, the cells were washed in FLIPR buffer (Hank's balanced salt solution free of calcium and magnesium, 10 mM HEPES, 2 mM CaCI ₂ , 2.5 mM probenePetition 870180137880, 10/04 / 2018, page 105/114

93/98 acid; FB). Each well received 100 pl of FB and 100 μΙ of the fluorescent dye AM Fluo-3 [2 μΜ of conc. Final]. After a 1 hour tincture load incubation at 37Ό, the cells were washed 4 times with FB, and a 75 μΙ / final well FB was left in each well.

[000492] Test compounds (dissolved in 10 mM DMSO and serially diluted with FB) or vehicle were added to each well (25 μΙ of a 4X solution) and allowed to equilibrate for 20 minutes in RT. The plates were then placed in the FLIPR and a baseline fluorescence measurement (excitation at 488 nm and emission at 510-570 nm) was obtained for 10 seconds before an addition of 100 μΙ / well of agonist or vehicle. The agonist was a 2X solution of α, β-meATP that produces a final concentration of 1 μΜ (P2X ₃ ) or 5 μΜ (P2X2 / 3). Fluorescence was measured for an additional 2 minutes at 1 second agonist addition intervals. A final addition of ionomycin (5 μΜ, final concentration) was made to each well of the FLIPR test plate to establish cell viability and maximum fluorescence of the cytosolic calcium bound to the dye. Peak fluorescence in response to the addition of α, β-meATP (in the absence and presence of test compounds) was measured and inhibition curves generated using non-linear regression. PPADS, a standard P2X antagonist, was used as a positive control.

[000493] Using the procedure above, the compounds of the invention exhibited activity for the P2X ₃ receptor. The 2'-fluoro-5- (5-isopropyl- [1,2,4] triazol-1-yl) -4'-methyl- ((S) -2-hydroxy-1-methylethyl) -amide biphenyl-3-carboxylic, for example, exhibited a pICso of about 8.77 for the P2X ₃ receptor, and the compound (1-pyrazin-2-yl-ethyl) -amide of 2'-fluoro-5- (5isopropyl- [1,2,4] triazole-1-yl) -4'-methyl-biphenyl-3-carboxylic showed a pKi of about 7.64 for the P2X2 / 3 receptor, using the assay above.

EXAMPLE 11: IN VIVO TEST FOR ASTHMA AND LUNG FUNCTION [000494] BALb / cJ mice are immunized with a standard immunization protocol. Briefly, mice (N = 8 / group) are immunized i.p. with ovalbumin (OVA; 10 pg) in alum on days 0 and 14. Mice are then challenged with aerosolized OVA (5%) on days 21 and 22.

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Animals receive vehicle (p.o.) or a compound of the invention (100 mg / kg p.o.) all starting on the 20th.

[000495] Lung function is assessed on day 23 using the Buxco system to measure PenH in response to an aerosol methacholine challenge. The mice are then euthanized and plasma samples taken at the end of the study.

EXAMPLE 12: VOLUME-INDUCED BLADDER CONTRACTION TEST [000496] Sprague-Dawley rats (200-300g) were anesthetized with urethane (1.5 g / kg, sc). The animals were tracheotomized, and a carotid artery and femoral vein were cannulated for blood pressure measurement and drug administration, respectively. A laparotomy was performed and the ureters were connected and transected close to the connection. The external urethral meatus was ligated with silk suture and the urinary bladder was cannulated through the dome for infusion of saline solution and measurement of bladder pressure.

[000497] Following a stabilization period of 15-30 minutes, the bladder was infused with 100 μΙ / min saline RT until continuous volume-induced bladder contractions (VIBCs) were observed. The infusion rate was then decreased to 3-5 μΙ / min for 30 minutes before the bladder was drained and allowed to rest for 30 minutes. All subsequent infusions were performed as directed except the lowest infusion rate was maintained for only 15 minutes instead of 30 minutes. Bladder filling and emptying cycles were repeated until the threshold volumes (TV; the volume needed to trigger the first bladder contraction by urination) varied by less than 10% for two successive baselines and the contraction frequency was within 2 contractions over a period of 10 minutes following the slowest infusion rate. Once reproducible TVs and VIBCs were established, the bladder was drained and the animal was dosed with drug or vehicle (0.5 ml / kg, i.v.) 3 minutes before the start of the next scheduled infusion.

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EXAMPLE 13: FORMALIN PAIN TEST [000498] Sprague-Dawley rats (180-220 g) are placed in individual Plexiglass cylinders and allowed to acclimate to the testing environment for 30 min. Vehicle, drug or positive control (morphine 2 mg / kg) is administered subcutaneously at 5 ml / kg. 15 min post-dosing, formalin (5% in 50 pl) is injected into the plantar surface of the right hind leg using a 26 gauge needle. The rats are immediately placed back in the observation chamber. Mirrors placed around the chamber allow free observation of the formalin-injected paw. The duration of each animal's harmful behavior is recorded by a blind observer using an automated behavior timer. Licking and shaking / raising the hind paw are recorded separately in 5 min in the compartment, for a total of 60 min. The sum of time spent licking or shaking in seconds of time 0 to 5 min is considered the premature phase, while the late phase is assumed to be the sum of seconds spent licking or shaking from 15 to 40 min. A sample of the plasma is taken.

EXAMPLE 14: COLON PAIN TEST [000499] Adult Sprague-Dawley rats (350-425 g; Harlan, Indianapolis, IN) are housed 1-2 per cage in an animal care facility. The rats are deeply anesthetized with pentobarbital sodium (45 mg / kg) administered intraperitoneally. Electrodes are placed and attached to the external oblique musculature for electromyographic recording (EMG). Lead electrode wires are channeled subcutaneously and externalized at the neck of the neck for future access. After surgery, the rats are housed separately and allowed to recover for 4-5 days before testing.

[000500] The descending colon and rectum are dilated by controlled pressure inflation from a 7-8 cm long flexible latex balloon tied around a flexible tube. The balloon is lubricated, inserted into the colon through the anus, and is moored by taping the balloon catheter to the base of the tail. Colorectal distention (CRD) is achieved by opening a gate

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96/98 solenoid for a constant pressure air reservoir. Intracolonic pressure is controlled and continuously monitored by a pressure control device. Response is quantified as the visceromotor response (VMR), a contraction of the abdominal muscles and the posterior limb. EMG activity produced by contraction of the external oblique musculature is quantified using Spike2 software (Cambridge Electronic Project). Each strain experiment lasts 60 s, and EMG activity is quantified for 20 s before strain (baseline), 20 s during strain, and 20 s after strain. The increase in the total number of counts recorded during stretching above the baseline is defined as the response. Stable baseline responses to CRD (10, 20, 40 and 80 mm of Hg, 20 seconds, 4 minutes separately) are obtained in conscious rats, not taken before any treatment.

[000501] The compounds are initially evaluated for effects on responses to colon distention in a model of acute visceral nociception and a model of colon hypersensitivity produced by intracolonic treatment with zymosan (1 ml, 25 mg / ml) instilled into the colon with a gavage needle inserted at a depth of about 6 cm. Experimental groups will consist of 8 rats each.

[000502] Acute visceral nociception: To test the effects of the drug on acute visceral nociception, 1 of 3 doses of drug, vehicle, or positive control (morphine, 2.5 mg / kg) are administered after baseline responses are established; responses to strain followed for the next 60-90 minutes.

[000503] Visceral hypersensitivity: To test the effects of the drug or vehicle after intracolonic treatment with zymosan, intracolonic treatment is given after baseline responses are established. Before testing the drug at 4 hours, responses are assessed for distension to establish the presence of hypersensitivity. In rats treated with zymosan, administration of 1 of 3 doses of drug, vehicle or positive control (morphine, 2.5 mg / kg) is given 4 hours after zymosan treatment and responses to the strain followed by the next 60-90 minutes.

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EXAMPLE 15: COLD ALLODINIA IN RATS WITH CHRONIC CONNECTION CONNECTION OF THE SCIATIC NERVE [000504] The effects of the compounds of this invention on cold allodynia are determined using the neuropathic pain model of chronic constriction injury (ICC) in rats, where cold allodynia is measured in a cold water bath with a metal plate floor and water at a depth of 1.5-2.0 cm and a temperature of 3-40 (Gogas, KR et al., Anal gesia, 1997 , 3, 1-8). [000505] Specifically, CCI rats are anesthetized; the sciatic nerve trifurcation is located and 4 ligatures (4-0, or 5-0 chrome catgut) are placed circumferentially around the sciatic nerve next to the trifurcation. The rats are then allowed to recover from the surgery. On days 4-7 after surgery, the rats are initially evaluated for cold-induced allodynia by placing the animals individually in the cold water bath and recording the total elevations of the injured paw over a period of 1 min: The injured paw is raised to out of the water. Paw elevations associated with locomotion or body repositioning are not recorded. Rats that exhibited 5 elevations per min or more on day 4-7 following surgery are considered to exhibit cold allodynia and are used in subsequent studies. In acute studies, vehicle, reference compound or compounds of this invention is administered subcutaneously (s.c.) 30 min before the test. The effects of repeated administration of the compounds of this invention in cold allodynia are determined at 14, 20 or 38 h following the last oral dose of the following regimen: oral administration (po) of vehicle, reference or a compound of this invention at ~ 12 intervals h (BID) for 7 days.

EXAMPLE 16: CANCER BONE PAIN IN C3H / HEJ MICE [000506] The effects of the compounds of this invention on bone pain are determined between Day 7 to Day 18 following intramedullary injection of sarcoma cells 2472 into the distal femur of the C3H / mice HeJ.

[000507] Specifically, tumor cells of NCTC 2472 (American

Type Culture Collection, ATCC), previously shown to form lytic lesions in bone after intramedullary injection, are cultured and maintained according to ATCC recommendations. Approximately 10 ⁵ cells are dirPetition 870180137880, from 10/04/2018, p. 110/114

98/98 injected into the medullary cavity of the distal femur in anesthetized C3H / HeJ mice. Beginning around Day 7, mice are evaluated for spontaneous nociceptive behaviors (rapid and intermittent elevation & watch), palpation evoked nociceptive behaviors (rapid and intermittent elevation & watch), forced ambulatory watch and paw use. The effects of the compounds of this invention are determined by following a simple acute (sc) administration on Day 7 - Day 15. In addition, the effects of repeated administration (BID) of the compounds of this invention from Day 7 - Day 15 are determined within 1 hour the first dose on Days 7,9, 11, 13 and 15.

[000508] Although the present invention has been described with reference to its specific modalities, it should be understood by those skilled in the art that various changes can be made and equivalents can be replaced without abandoning the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, substance composition, process, stage or stages of the process, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims attached here.

Claims (2)

1. Compound, characterized by the fact that it is selected from the group consisting of: 4'-methyl5- [1,2,3] triazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide; 4'-methyl5- (5-methyl- [1,2,3] triazol-2-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide; 4'-methyl5- (5-methyl- [1,2,3] triazol-2-yl-biphenyl-3-carboxylic acid ((r) -2-methoxy-1-methyl-ethyl) -amide; 5- (5-Isopropyl [1.2.4] tri-azo-1-yl) -4'-methyl-1-biphenyl-3-carboxylic acid ((s) -2-hydroxy-1-methyl-ethyl) -amide ; 5- (5-Isopropyl [1.2.4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl) -amide; 5- (5-Isopropyl [1.2.4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid ((r) -2-hydroxy-1-methyl-ethyl) -amide; 5- (5-Isopropyl [1.2.4] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide; 4'-methyl5- (5-methyl- [1,2,3] triazol-2-yl-biphenyl-3-carboxylic acid ((s) -2-hydroxy-1-methyl-ethyl) -amide; 2'-fluoro-5- (5isopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl- ((r) -2-methoxy-1-methyl-ethyl) -amide 3-carboxylic; 2'-fluoro-5- (5isopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl) -amide; 2'-fluoro-5- (5isopropyl- [1,2,3] triazol-1-yl) -4'-methyl-biphenyl- ((r) -2-hydroxy-1-methyl-ethyl) -amide 3-carboxylic. 2. Use of a compound, as defined in claim 1, characterized by the fact that it is in the preparation of a medication for the treatment of an inflammatory and / or autoimmune pain condition, which is selected from inflammatory pain, surgical pain, visceral pain , dental pain, premenstrual pain, central pain, pain due to burns, Petition 870190026544, of 03/20/2019, p. 4/9 2/2 migraine or cluster headaches, nerve damage, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury, or pain associated with irritable bowel syndrome , or a respiratory disorder selected from chronic obstructive pulmonary disorder (COPD), asthma, and bronchospasm.